Hexahydrodiazepinoquinolines carrying a substituted alkyl radical

ABSTRACT

The present invention relates to tricyclic hexahydrodiazepinoquinolines carrying a substituted alkyl radical, to a method for producing them, to a pharmaceutical composition containing such compounds, to their use as modulators, especially agonists or partial agonists, of the 5-HT 2C  receptor, their use for preparing a medicament for the prevention or treatment of conditions and disorders which respond to the modulation of 5-HT 2C  receptor, to a method for preventing or treating conditions and disorders which respond to the modulation of 5-HT 2C  receptor, and processes for preparing such compounds and compositions.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This claims priority to U.S. Provisional Patent Application No.61/953,337, filed on Mar. 14, 2014, the entire contents of which arefully incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to tricyclic hexahydrodiazepinoquinolinescarrying a substituted alkyl radical, to a method for producing them, toa pharmaceutical composition containing such compounds, to their use asmodulators, especially agonists or partial agonists, of the 5-HT_(2C)receptor, their use for preparing a medicament for the prevention ortreatment of conditions and disorders which respond to the modulation of5-HT_(2C) receptor, to a method for preventing or treating conditionsand disorders which respond to the modulation of 5-HT_(2C) receptor, andprocesses for preparing such compounds and compositions.

BACKGROUND OF THE INVENTION

Diseases, disorders and conditions where 5-HT_(2C) modulation is desiredare for example depression, anxiety, schizophrenia, bipolar disorder,obsessive compulsive disorder, migraine, pain, epilepsy, substanceabuse, eating disorders, obesity, diabetes, erectile dysfunction andothers.

Serotonin (5-hydroxytryptamine, 5-HT), a monoamine neurotransmitter andlocal hormone, is formed by the hydroxylation and decarboxylation oftryptophan. The greatest concentration is found in the enterochromaffincells of the gastrointestinal tract, the remainder being predominantlypresent in platelets and in the Central Nervous System (CNS). 5-HT isimplicated in a vast array of physiological and pathophysiologicalpathways. In the periphery, it contracts a number of smooth muscles andinduces endothelium-dependent vasodilation. In the CNS, it is believedto be involved in a wide range of functions, including the control ofappetite, mood, anxiety, hallucinations, sleep, vomiting and painperception.

Neurons that secrete 5-HT are termed serotonergic. The function of 5-HTis exerted upon its interaction with specific (serotonergic) neurons.Seven types of 5-HT receptors have been identified: 5-HT₁ (with subtypes5-HT_(1A), 5-HT_(1B), 5-HT_(1D), 5-HT_(1E) and 5-HT_(1F)), 5-HT₂ (withsubtypes 5-HT_(2A), 5-HT_(2B) and 5-HT_(2C)), 5-HT₃, 5-HT₄, 5-HT₅ (withsubtypes 5-HT_(5A) and 5-HT_(5B)), 5-HT₆ and 5-HT₇. Most of thesereceptors are coupled to G-proteins that affect the activities ofadenylate cyclase or phospholipase Cγ.

Alterations in the activity of multiple neurotransmitter receptorsystems (dopamine, serotonin, glutamate, GABA, acetylcholine) have beenimplicated in the manifestation of the symptoms of schizophrenia. Themost widely accepted “Dopamine Hypothesis of Schizophrenia” in itssimplest form states that the positive symptoms of this pathology relateto a functional hyperactivity of the mesolimbic dopaminergic system,while the negative and cognitive aspects can be traced to a functionalhypoactivity of the mesocortical dopaminergic projections. Atypicalantipsychotics block the mesolimbic dopaminergic neurotransmission,thereby controlling positive symptoms, with little or no effect on thenigrostriatal system, leading to less induction of extrapyramidal sideeffects (EPS).

Primary negative and cognitive symptoms of schizophrenia reflect adysfunction of the frontal cortex (“hypofrontality”), which is thoughtto be induced by a decreased tone in the mesocortical dopaminergicprojection field [Davis K L, Kahn R S, Ko G and Davidson M (1991).Dopamine in schizophrenia: a review and re-conceptualization. Am JPsychiatry 148: 1474-86. Weinberger D R and Berman K F (1996).Prefrontal function in schizophrenia: confounds and controversies.Philos Trans R Soc Lond B Biol Sci 351: 1495-503]. Agents thatselectively enhance dopamine levels in the cortex have the potential toaddress the negative symptoms of this disorder. Atypical antipsychoticslack robust efficacy against negative and cognitive components of theschizophrenic syndrome.

The schizophrenic symptomatology is further complicated by theoccurrence of drug-induced so-called secondary negative symptoms andcognitive impairment, which are difficult to distinguish from primarynegative and cognitive symptoms [Remington G and Kapur S (2000).Atypical antipsychotics: are some more atypical than others?Psychopharmacol 148: 3-15]. The occurrence of secondary negativesymptoms not only limits therapeutic efficacy but also, together withthese side effects, negatively affects patient compliance.

It may thus be hypothesized that a novel mechanistic approach thatblocks dopaminergic neurotransmission in the limbic system but does notaffect the striatal and pituitary projection fields, and stimulatesfrontocortical projection fields, would provide an efficacious treatmentfor all parts of the schizophrenic pathology, including its positive,negative and cognitive symptoms. Moreover, a selective compound that issubstantially free of the ancillary pharmacology that characterizescurrent agents would be expected to avoid a variety of off-target sideeffects that plague current treatments such as extrapyramidal sideeffects (EPS) and weight gain.

The 5-HT_(2C) receptor, previously named 5-HT1C, is a G-protein-coupledreceptor, which couples to multiple cellular effector systems includingthe phospholipase C, A and D pathways. It is found primarily in thebrain and its distribution is particularly high in the plexuschoroideus, where it is assumed to control cerebrospinal fluidproduction [Kaufman M J, Hirata F (1996) Cyclic GMP inhibitsphosphoinositide turnover in choroid plexus: evidence for interactionsbetween second messengers concurrently triggered by 5-HT_(2C) receptors.Neurosci Lett 206:153-156]. Very high levels were also found in theretrosplenial, piriform and entorhinal cortex, anterior olfactorynucleus, lateral septal nucleus, subthalamic nucleus, amygdala,subiculum and ventral part of CA3, lateral habenula, substantia nigrapars compacta, several brainstem nuclei and the whole grey matter of thespinal cord [Pompeiano M, Palacios J M, Mengod G (1994). Distribution ofthe serotonin 5-HT2 receptor family mRNAs: comparison between 5-HT_(2A)and 5-HT_(2C) receptors. Brain Res Mol Brain Res 23:163-178]. Acomparison of the distribution of 5-HT_(2C) mRNA with that of 5-HT_(2C)protein in monkey and human brains has revealed both pre- andpostsynaptic localization [Lopez-Gimenez J F, Mengod G, Palacios J M,Vilaro M T (2001) Regional distribution and cellular localization of5-HT_(2C) receptor mRNA in monkey brain: comparison with [³H]mesulerginebinding sites and choline acetyltransferase mRNA. Synapse 42:12-26].

It is anticipated that modulation of the 5-HT_(2C) receptor will improvedisorders such as depression, anxiety, schizophrenia, cognitive deficitsof schizophrenia, obsessive compulsive disorder, bipolar disorder,neuropsychiatric symptoms in Parkinson' disease, in Alzheimer's diseaseor Lewy Body dementia, migraine, epilepsy, substance abuse, eatingdisorders, obesity, diabetes, sexual dysfunction/erectile dysfunction,sleep disorders, psoriasis, Parkinson's disease, pain conditions anddisorders, and spinal cord injury, smoking cessation, ocularhypertension and Alzheimer's disease. Modulators of the 5-HT_(2C)receptor are also shown to be useful in the modulation of bladderfunction, including the prevention or treatment of urinary incontinence.

Compounds with a structure similar to the compounds of the presentinvention have been described in WO 2014/041131 and WO 03/091250.

There is an ongoing need for providing compounds having high affinityand in particular also high selectivity for the 5-HT_(2C) receptor. Inparticular the compounds should have low affinity to adrenergicreceptors, such as the α₁-adrenergic receptor, histamine receptors, suchas the H₁-receptor, and dopaminergic receptors, such as the D₂-receptor,in order to avoid or reduce side effects associated with modulation ofthese receptors, such as postural hypotension, reflex tachycardia,potentiation of the antihypertensive effect of prazosin, terazosin,doxazosin and labetalol or dizziness associated with the blockade of theα₁-adrenergic receptor, weight gain, sedation, drowsiness orpotentiation of central depressant drugs associated with the blockade ofthe H₁-receptor, or extrapyramidal movement disorder, such as dystonia,parkinsonism, akathisia, tardive dyskinesia or rabbit syndrome, orendocrine effects, such as prolactin elevation (galactorrhea,gynecomastia, mentstrual changes, sexual dysfunction in males),associated with the blockade of the D₂-receptor, and even more importantno induction of weight gain in combination with severe metabolicdysfunction found for marketed antipsychotic drugs.

It is moreover desirable that the compounds have low affinity oralternatively an antagonistic effect to/on other serotonergic receptors,especially the 5-HT_(2A) and/or 5-HT_(2B) receptors, in order to avoidor reduce side effects associated with modulation of these receptors,such as changes (thickening) of the heart tissue associated with agonismat the 5-HT_(2B) receptor, and psychotomimetic effect induced by agonismat the 5-HT_(2A) receptor. Ideally they should show an agonistic actionon the 5-HT_(2C) receptor, an antagonistic action on the 5-HT_(2A)receptor or alternatively no affinity to the 5-HT_(2A) receptor and noaffinity to the 5-HT_(2B) receptor or alternatively an antagonisticaction on the 5-HT_(2B) receptor. Even more ideally the compounds shoulddisplay an agonistic action on the 5-HT_(2C) receptor in combinationwith an antagonistic action on the 5-HT_(2A) receptor and no affinity tothe 5-HT_(2B) receptor.

Besides the affinity and selectivity for the 5-HT_(2C) receptor, furtherproperties may be advantageous for the treatment and/or prophylaxis of5-HT_(2C)-related disorders, such as, for example:

1.) the metabolic stability, for example determined from the half-lives,measured in vitro, in liver microsomes from various species (e.g. rat orhuman);

2.) no or only low inhibition of cytochrome P450 (CYP) enzymes:cytochrome P450 (CYP) is the name for a superfamily of heme proteinshaving enzymatic activity (oxidase). They are also particularlyimportant for the degradation (metabolism) of foreign substances such asdrugs or xenobiotics in mammalian organisms. The principalrepresentatives of the types and subtypes of CYP in the human body are:CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. If CYP 3A4 inhibitors (e.g.grapefruit juice, cimetidine, erythromycin) are used at the same time asmedicinal substances which are degraded by this enzyme system and thuscompete for the same binding site on the enzyme, the degradation thereofmay be slowed down and thus effects and side effects of the administeredmedicinal substance may be undesirably enhanced;

3.) a suitable solubility in water (in mg/mL);

4.) suitable pharmacokinetics (time course of the concentration of thecompound of the invention in plasma or in tissue, for example brain).The pharmacokinetics can be described by the following parameters:half-life (in h), volume of distribution (in 1·kg−1), plasma clearance(in 1·h−1·kg−1), AUC (area under the curve, area under theconcentration-time curve, in ng·h·1−1), oral bioavailability (thedose-normalized ratio of AUC after oral administration and AUC afterintravenous administration), the so-called brain-plasma ratio (the ratioof AUC in brain tissue and AUC in plasma);

5.) no or only low blockade of the hERG channel: compounds which blockthe hERG channel may cause a prolongation of the QT interval and thuslead to serious disturbances of cardiac rhythm (for example so-called“torsade de pointes”). The potential of compounds to block the hERGchannel can be determined by means of the displacement assay withradiolabelled dofetilide which is described in the literature (G. J.Diaz et al., Journal of Pharmacological and Toxicological Methods, 50(2004), 187 199). A smaller IC50 in this dofetilide assay means agreater probability of potent hERG blockade. In addition, the blockadeof the hERG channel can be measured by electrophysiological experimentson cells which have been transfected with the hERG channel, by so-calledwhole-cell patch clamping (G. J. Diaz et al., Journal of Pharmacologicaland Toxicological Methods, 50 (2004), 187-199).

It was an object of the present invention to provide compounds for thetreatment or prophylaxis of various 5-HT_(2C)-related diseases. Thecompounds were intended to have a high affinity on the 5-HT_(2C)receptor and be potent and efficacious 5-HT_(2C) agonists. In addition,the compounds of the invention were intended to have one or more of theaforementioned advantages, namely low affinity to other serotonergicreceptors, and especially the lack of potent agonistic effect(antagonism preferred) on the 5-HT_(2A) and/or 5-HT_(2B) receptors, andadditionally one or more of those advantages mentioned under 1.) to 5.).

The present invention provides compounds which have an affinity for the5-HT_(2C), thus allowing the treatment of disorders related to oraffected by the 5-HT_(2C) receptor.

SUMMARY OF THE INVENTION

The present invention relates to tricyclic hexahydrodiazepinoquinolinescarrying a substituted alkyl radical, to a method for producing them, tocompositions comprising such compounds, their use as modulators,especially agonists or partial agonists, of the 5-HT_(2C) receptor,their use for preparing a medicament for the prevention or treatment ofconditions and disorders which respond to the modulation of 5-HT_(2C)receptor, to a method for preventing or treating conditions anddisorders which respond to the modulation of 5-HT_(2C) receptor, andprocesses for preparing such compounds and compositions.

In one aspect, the present invention relates to compounds of the formula(I):

wherein

-   R¹ is selected from the group consisting of hydrogen, cyano,    C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl, fluorinated    C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,    fluorinated C₁-C₆-alkoxy, —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl and a    3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or    maximally unsaturated heterocyclic ring containing 1, 2, 3 or 4    heteroatoms or heteroatom groups independently selected from N, O,    S, NO, SO and SO₂ and optionally also 1 or 2 C═O and/or C═S groups    as ring members, where the cyclic moieties in the three    last-mentioned radicals may be substituted with one or more    substituents R¹⁰;-   each R² is independently selected from the group consisting of    cyano, nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,    C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl,    C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl,    fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated    C₁-C₆-alkoxy-C₁-C₄-alkyl, —CH₂NR^(11a)R^(11b), —C(═O)R⁹, phenyl,    phenyl-C₁-C₂-alkyl, and a 3-, 4-, 5-, 6-, 7- or 8-membered    saturated, partially unsaturated or maximally unsaturated ring    containing 1, 2, 3 or 4 heteroatoms or heteroatom groups    independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as    ring members, where the cyclic moieties in the six last-mentioned    radicals may be substituted with one or more substituents R¹⁰; or    -   two radicals R² bound to the same carbon atom, together with the        carbon atom they are bound to, form a 3-, 4-, 5-, 6-, 7- or        8-membered saturated, partially unsaturated or maximally        unsaturated ring (i.e. a spiro-bound ring), where the ring may        contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups        selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and        where the ring may be substituted with one or more substituents        R¹⁰;-   R^(3a) and R^(3b), independently of each other, are selected from    the group consisting of hydrogen, cyano, nitro, C₁-C₆-alkyl,    fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl,    fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,    C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl,    —CH₂NR^(11a)R^(11b), —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl, and a 3-,    4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or    maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or    heteroatom groups independently selected from N, O, S, NO, SO, SO₂,    C═O and C═S as ring members, where the cyclic moieties in the six    last-mentioned radicals may be substituted with one or more    substituents R¹⁰;-   R^(4a) and R^(4b), independently of each other, are selected from    the group consisting of hydrogen, cyano, nitro, C₁-C₆-alkyl,    fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl,    fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,    C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl,    —CH₂NR^(11a)R^(11b), —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl, and a 3-,    4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or    maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or    heteroatom groups independently selected from N, O, S, NO, SO, SO₂,    C═O and C═S as ring members, where the cyclic moieties in the six    last-mentioned radicals may be substituted with one or more    substituents R¹⁰; or    -   R^(4a) and R^(4b) form together a group ═O or ═S; or    -   R^(4a) and R^(4b), together with the carbon atom they are bound        to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially        unsaturated or maximally unsaturated ring (i.e. a spiro-bound        ring), where the ring may contain 1, 2, 3 or 4 heteroatoms or        heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O        and C═S as ring members, and where the ring may be substituted        with one or more substituents R¹⁰;-   R^(5a) and R^(5b), independently of each other, are selected from    the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl,    C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl,    C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated    C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,    C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl,    fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-hydroxyalkoxy,    C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated    C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl, —NR^(11a)R^(11b), —CH₂NR^(11a)R^(11b),    —NR^(11a)C(O)R⁹, —C(═O)R⁹, SO₂NR^(11a)R^(11b),    C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy, phenyl,    phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-,    5-, 6-, 7- or 8-membered saturated, partially unsaturated or    maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or    heteroatom groups independently selected from N, O, S, NO, SO, SO₂,    C═O and C═S as ring members, where the cyclic moieties in the six    last-mentioned radicals may be substituted with one or more    substituents R¹⁰; where    -   R^(5a) and R^(5b) are not simultaneously hydroxyl; or    -   R^(5a) and R^(5b), together with the carbon atom they are bound        to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially        unsaturated or maximally unsaturated ring (i.e. a spiro-bound        ring), where the ring may contain 1, 2, 3 or 4 heteroatoms or        heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O        and C═S as ring members, and where the ring may be substituted        with one or more substituents R¹⁰;-   R⁶ C₁-C₆-alkyl which carries one or more substituents R⁸;-   each R⁷ is independently selected from the group consisting of    halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl, fluorinated    C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated    C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl,    fluorinated C₃-C₈-cycloalkenyl, C₁-C₆-alkoxy, fluorinated    C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated    C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-hydroxyalkoxy,    C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated    C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl, —NR^(11a)R^(11b), —CH₂NR^(11a)R^(11b),    —NR^(11a)C(O)R⁹, —C(═O)R⁹, SO₂NR^(11a)R^(11b),    C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy, phenyl,    phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-,    5-, 6-, 7- or 8-membered saturated, partially unsaturated or    maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or    heteroatom groups independently selected from N, O, S, NO, SO, SO₂,    C═O and C═S as ring members, where the cyclic moieties in the six    last-mentioned radicals may be substituted with one or more    substituents R¹⁰; or    -   two radicals R⁷ bound on neighboring carbon atoms, together with        the carbon atoms they are bound to, form a 3-, 4-, 5-, 6-, 7- or        8-membered partially unsaturated or maximally unsaturated ring,        where the ring may contain 1, 2, 3 or 4 heteroatoms or        heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O        and C═S as ring members, and where the ring may be substituted        with one or more substituents R¹⁰;-   each R⁸ is independently selected from the group consisting of    hydroxyl, halogen, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy,    C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio,    fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl and —NR^(11a)R^(11b);-   each R⁹ is independently selected from the group consisting of    hydrogen, cyano, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,    C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl,    C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl,    fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated    C₁-C₆-alkoxy, —NR^(11a)R^(11b), —CH₂NR^(11a)R^(11b), phenyl,    phenyl-C₁-C₂-alkyl, phenoxy, benzyloxy and a 3-, 4-, 5-, 6-, 7- or    8-membered saturated, partially unsaturated or maximally unsaturated    ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups    independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as    ring members, where the cyclic moieties in the five last-mentioned    radicals may be substituted with one or more substituents R¹⁰;-   each R¹⁰ is independently selected from the group consisting of    halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl, fluorinated    C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated    C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,    C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,    fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated    C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-hydroxyalkoxy,    C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated    C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated    C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated    C₁-C₆-alkylsulfonyl, —COOH, —NR^(11a)R^(11b), —CH₂NR^(11a)R^(11b),    C₁-C₆-alkylcarbonyl, fluorinated C₁-C₆-alkylcarbonyl,    C₁-C₆-alkoxycarbonyl, fluorinated C₁-C₆-alkoxycarbonyl,    SO₂NR^(11a)R^(11b), C₁-C₆-alkylcarbonyloxy and fluorinated    C₁-C₆-alkylcarbonyloxy;    -   or two radicals R¹⁰, together with the atom(s) they are bound        to, form a saturated, partially unsaturated or maximally        unsaturated 3-, 4-, 5-, 6- or 7-membered carbocyclic or        heterocyclic ring, where the heterocyclic ring contains 1, 2 or        3 heteroatoms or heteroatom groups independently selected from        N, O, S, NO, SO, SO₂, C═O and C═S as ring members;-   R^(11a) and R^(11b), independently of each other and independently    of each occurrence, are selected from the group consisting of    hydrogen, cyano, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,    C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated    C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,    C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl,    fluorinated C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, fluorinated    C₁-C₆-alkoxycarbonyl, phenyl and benzyl, where the phenyl moieties    in the two last-mentioned radicals may carry 1, 2 or 3 substituents    selected from halogen, cyano nitro, C₁-C₆-alkyl, fluorinated    C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy; or,    -   if R^(11a) and R^(11b) are bound to the same nitrogen atom,        together with this nitrogen atom may form a 3-, 4-, 5-, 6-, 7-        or 8-membered saturated, partially unsaturated or maximally        unsaturated heterocyclic ring, where the ring may further        contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups        selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and        where the ring may be substituted with one or more substituents        selected from halogen, cyano nitro, C₁-C₆-alkyl, fluorinated        C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy;-   a is 0, 1 or 2; and-   b is 0, 1, 2 or 3;-   or an N-oxide, a tautomeric form, a stereoisomer or a    pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to a pharmaceutical compositioncomprising a therapeutically effective amount of at least one compoundof formula I or an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof, in combination with at leastone pharmaceutically acceptable carrier and/or auxiliary substance.

In yet another aspect, the invention relates to a compound of formula Ior an N-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof for use as a medicament.

In yet another aspect, the invention relates to a compound of formula Ior an N-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof for the treatment of disorders which responds tothe modulation of the 5-HT_(2C) receptor.

In yet another aspect, the invention relates to the use of a compound offormula I or of an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of disorders which respond to themodulation of the 5-HT_(2C) receptor.

In yet another aspect, the invention relates to the use of a compound offormula I or of an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of disorders selected from the groupconsisting of damage of the central nervous system, disorders of thecentral nervous system, eating disorders, ocular hypertension,cardiovascular disorders, gastrointestinal disorders and diabetes, andespecially from the group consisting of bipolar disorder, depression,atypical depression, mood episodes, adjustment disorders, anxiety, panicdisorders, post-traumatic syndrome, psychoses, schizophrenia, cognitivedeficits of schizophrenia, memory loss, dementia of aging, Alzheimer'sdisease, neuropsychiatric symptoms in Alzheimer's disease (e.g.aggression), behavioral disorders associated with dementia, socialphobia, mental disorders in childhood, attention deficit hyperactivitydisorder, organic mental disorders, autism, mutism, disruptive behaviordisorder, impulse control disorder, borderline personality disorder,obsessive compulsive disorder, migraine and other conditions associatedwith cephalic pain or other pain, raised intracranial pressure, seizuredisorders, epilepsy, substance use disorders, alcohol abuse, cocaineabuse, tobacco abuse, smoking cessation, sexual dysfunction/erectiledysfunction in males, sexual dysfunction in females, premenstrualsyndrome, late luteal phase syndrome, chronic fatigue syndrome, sleepdisorders, sleep apnoea, chronic fatigue syndrome, psoriasis,Parkinson's disease, neuropsychiatric symptoms in Parkinson's disease(e.g. aggression), Lewy Body dementia, neuropsychiatric symptoms in LewyBody dementia (e.g. aggression), spinal cord injury, trauma, stroke,pain, bladder dysfunction/urinary incontinence, encephalitis,meningitis, eating disorders, obesity, bulimia, weight loss, anorexianervosa, ocular hypertension, cardiovascular disorders, gastrointestinaldisorders, diabetes insipidus, diabetes mellitus, type I diabetes, typeII diabetes, type III diabetes, diabetes secondary to pancreaticdiseases, diabetes related to steroid use, diabetes complications,hyperglycemia and insulin resistance.

In yet another aspect, the invention relates to a method for treatingdisorders which respond to the modulation of the 5-HT_(2C) receptor,which method comprises administering to a subject in need thereof atleast one compound of formula I or an N-oxide, a tautomeric form, astereoisomer or a pharmaceutically acceptable salt thereof.

In yet another aspect, the invention relates to a method for treatingdisorders selected from the group consisting of damage of the centralnervous system, disorders of the central nervous system, eatingdisorders, ocular hypertension, cardiovascular disorders,gastrointestinal disorders and diabetes, and especially from the groupconsisting of bipolar disorder, depression, atypical depression, moodepisodes, adjustment disorders, anxiety, panic disorders, post-traumaticsyndrome, psychoses, schizophrenia, cognitive deficits of schizophrenia,memory loss, dementia of aging, Alzheimer's disease, neuropsychiatricsymptoms in Alzheimer's disease (e.g. aggression), behavioral disordersassociated with dementia, social phobia, mental disorders in childhood,attention deficit hyperactivity disorder, organic mental disorders,autism, mutism, disruptive behavior disorder, impulse control disorder,borderline personality disorder, obsessive compulsive disorder, migraineand other conditions associated with cephalic pain or other pain, raisedintracranial pressure, seizure disorders, epilepsy, substance usedisorders, alcohol abuse, cocaine abuse, tobacco abuse, smokingcessation, sexual dysfunction/erectile dysfunction in males, sexualdysfunction in females, premenstrual syndrome, late luteal phasesyndrome, chronic fatigue syndrome, sleep disorders, sleep apnoea,chronic fatigue syndrome, psoriasis, Parkinson's disease,neuropsychiatric symptoms in Parkinson's disease (e.g. aggression), LewyBody dementia, neuropsychiatric symptoms in Lewy Body dementia (e.g.aggression), spinal cord injury, trauma, stroke, pain, bladderdysfunction/urinary incontinence, encephalitis, meningitis, eatingdisorders, obesity, bulimia, weight loss, anorexia nervosa, ocularhypertension, cardiovascular disorders, gastrointestinal disorders,diabetes insipidus, diabetes mellitus, type I diabetes, type IIdiabetes, type III diabetes, diabetes secondary to pancreatic diseases,diabetes related to steroid use, diabetes complications, hyperglycemiaand insulin resistance, which method comprises administering to asubject in need thereof at least one compound of formula I or anN-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof.

DETAILED DESCRIPTION

The compounds of the formula I may exist in different spatialarrangements. For example, if the compounds possess one or more centersof asymmetry, polysubstituted rings or double bonds, or as differenttautomers, the present invention contemplates the possible use ofenantiomeric mixtures, in particular racemates, diastereomeric mixturesand tautomeric mixtures, such as the respective essentially pureenantiomers, diastereomers and tautomers of the compounds of formula Iand/or their salts.

It is likewise possible to use physiologically tolerated salts of thecompounds of the formula I, especially acid addition salts withphysiologically tolerated acids. Examples of suitable physiologicallytolerated organic and inorganic acids are hydrochloric acid, hydrobromicacid, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid,C₁-C₄-alkylsulfonic acids, such as methanesulfonic acid, aromaticsulfonic acids, such as benzenesulfonic acid and toluenesulfonic acid,oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid,adipic acid and benzoic acid. Other utilizable acids are described inFortschritte der Arzneimittelforschung [Advances in drug research],Volume 10, pages 224 et seq., Birkhäuser Verlag, Basel and Stuttgart,1966.

The compounds of formula I may also be present in the form of tautomers.In one aspect, tautomery may be present in compounds I wherein R^(4a)and R^(4b) form together a group ═O and R^(5a) or R^(5b) is H. Forexample, the compounds of formula I may have the following tautomericformulae:

In another aspect, tautomery may be present in compounds I containingrings which have one or more C═O groups as ring members which areneighboured to a CH₂ group.

The organic moieties mentioned in the above definitions of the variablesare, like the term halogen, collective terms for individual listings ofthe individual group members. The prefix C_(n)-C_(m) indicates in eachcase the possible number of carbon atoms in the group.

The term “halogen” denotes in each case fluorine, bromine, chlorine oriodine. In one aspect, the halogen may be fluorine, chlorine or bromine.

The term “alkyl” as used herein and in the alkyl moieties of alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyland the like refers to saturated straight-chain or branched hydrocarbonradicals having 1 to 2 (“C₁-C₂-alkyl”), 1 to 3 (“C₁-C₃-alkyl”), 1 to 4(“C₁-C₄-alkyl”) or 1 to 6 (“C₁-C₆-alkyl”) carbon atoms. C₁-C₂-Alkyl ismethyl or ethyl. C₁-C₃-Alkyl is additionally propyl and isopropyl.C₁-C₄-Alkyl is additionally butyl, 1-methylpropyl (sec-butyl),2-methylpropyl (isobutyl) or 1,1-dimethylethyl (tert-butyl). C₁-C₆-Alkylis additionally also, for example, pentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or1-ethyl-2-methylpropyl.

The term “fluorinated alkyl” as used herein refers to straight-chain orbranched alkyl groups having 1 (“fluorinated methyl), 1 to 2(“fluorinated C₁-C₂-alkyl”), 1 to 3 (“fluorinated C₁-C₃-alkyl”), 1 to 4(“fluorinated C₁-C₄-alkyl”) or 1 to 6 (“fluorinated C₁-C₆-alkyl”) carbonatoms (as mentioned above), where some or all of the hydrogen atoms inthese groups are replaced by fluorine atoms. Fluorinated methyl isfluoromethyl, difluoromethyl or trifluoromethyl. Fluorinated C₁-C₂-alkylis an alkyl group having 1 or 2 carbon atoms (as mentioned above), whereat least one of the hydrogen atoms, e.g. 1, 2, 3, 4 or 5 hydrogen atomsin these groups are replaced by fluorine atoms, such as difluoromethyl,trifluoromethyl, 1-fluoroethyl, (R)-1-fluoroethyl, (S)-1-fluoroethyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, orpentafluoroethyl. Fluorinated C₁-C₄-alkyl is a straight-chain orbranched alkyl group having 1 to 4 carbon atoms (as mentioned above),where at least one of the hydrogen atoms, e.g. 1, 2, 3, 4 or 5 hydrogenatoms in these groups are replaced by fluorine atoms. Examples are,apart those listed above for C₁-C₂-fluoroalkyl, 1-fluoropropyl,(R)-1-fluoropropyl, (S)-1-fluoropropyl, 2-fluoropropyl,(R)-2-fluoropropyl, (S)-2-fluoropropyl, 3-fluoropropyl,1,1-difluoropropyl, 2,2-difluoropropyl, 1,2-difluoropropyl,2,3-difluoropropyl, 1,3-difluoropropyl, 3,3-difluoropropyl,1,1,2-trifluoropropyl, 1,2,2-trifluoropropyl, 1,2,3-trifluoropropyl,2,2,3-trifluoropropyl, 3,3,3-trifluoropropyl, 1,1,1-trifluoroprop-2-yl,2-fluoro-1-methylethyl, (R)-2-fluoro-1-methylethyl,(S)-2-fluoro-1-methylethyl, 2,2-difluoro-1-methylethyl,(R)-2,2-difluoro-1-methylethyl, (S)-2,2-difluoro-1-methylethyl,1,2-difluoro-1-methylethyl, (R)-1,2-difluoro-1-methylethyl,(S)-1,2-difluoro-1-methylethyl, 2,2,2-trifluoro-1-methylethyl,(R)-2,2,2-trifluoro-1-methylethyl, (S)-2,2,2-trifluoro-1-methylethyl,2-fluoro-1-(fluoromethyl)ethyl, 1-(difluoromethyl)-2,2-difluoroethyl,1-(trifluoromethyl)-2,2,2-trifluoroethyl,1-(trifluoromethyl)-1,2,2,2-tetrafluoroethyl, 1-fluorobutyl,(R)-1-fluorobutyl, (S)-1-fluorobutyl, 2-fluorobutyl, (R)-2-fluorobutyl,(S)-2-fluorobutyl, 3-fluorobutyl, (R)-3-fluorobutyl, (S)-3-fluorobutyl,4-fluorobutyl, 1,1-difluorobutyl, 2,2-difluorobutyl, 3,3-difluorobutyl,4,4-difluorobutyl, 4,4,4-trifluorobutyl and the like. FluorinatedC₁-C₆-alkyl is a straight-chain or branched alkyl group having 1 to 6carbon atoms (as mentioned above), where at least one of the hydrogenatoms, e.g. 1, 2, 3, 4 or 5 hydrogen atoms in these groups are replacedby fluorine atoms. Additionally examples include for C₁-C₄-fluoroalkyl,1-fluoropentyl, (R)-1-fluoropentyl, (S)-1-fluoropentyl, 2-fluoropentyl,(R)-2-fluoropentyl, (S)-2-fluoropentyl, 3-fluoropentyl,(R)-3-fluoropentyl, (S)-3-fluoropentyl, 4-fluoropentyl,(R)-4-fluoropentyl, (S)-4-fluoropentyl, 5-fluoropentyl,(R)-5-fluoropentyl, (S)-5-fluoropentyl, 1-fluorohexyl,(R)-1-fluorohexyl, (S)-1-fluorohexyl, 2-fluorohexyl, (R)-2-fluorohexyl,(S)-2-fluorohexyl, 3-fluorohexyl, (R)-3-fluorohexyl, (S)-3-fluorohexyl,4-fluorohexyl, (R)-4-fluorohexyl, (S)-4-fluorohexyl, 5-fluorohexyl,(R)-5-fluorohexyl, (S)-5-fluorohexyl, 6-fluorohexyl, (R)-6-fluorohexyl,(S)-6-fluorohexyl, and the like.

The term “haloalkyl” as used herein refers to straight-chain or branchedalkyl groups having 1 to 2 (“C₁-C₂-haloalkyl”), 1 to 3(“C₁-C₃-haloalkyl”), 1 to 4 (“C₁-C₄-haloalkyl”) or 1 to 6(“C₁-C₆-haloalkyl”) carbon atoms (as mentioned above), where some or allof the hydrogen atoms in these groups are replaced by halogen atoms asmentioned above. Examples are, apart from those mentioned above forfluorinated alkyl, for C₁-C₂-haloalkyl chloromethyl, bromomethyl,dichloromethyl, trichloromethyl, chlorofluoromethyl,dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl,2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl,2,2-dichloro-2-fluoroethyl or 2,2,2-trichloroethyl; for C₁-C₃-haloalkyl,apart those mentioned for C₁-C₂-haloalkyl, 3-chloropropyl; and forC₁-C₄-haloalkyl, apart those mentioned for C₁-C₃-haloalkyl,4-chlorobutyl and the like.

The term “alkenyl” as used herein refers to monounsaturatedstraight-chain or branched hydrocarbon radicals having 2 to 3(“C₂-C₃-alkenyl”), 2 to 4 (“C₂-C₄-alkenyl”) or 2 to 6 (“C₂-C₆-alkenyl”)carbon atoms and a double bond in any position, such as C₂-C₃-alkenyl,such as ethenyl, 1-propenyl, 2-propenyl or 1-methylethenyl;C₂-C₄-alkenyl, such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl,1-butenyl, 2-butenyl, 3-butenyl, 1-methyl -1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl or 2-methyl-2-propenyl; andC₂-C₆-alkenyl, such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl,1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl,2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl,2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl,2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl,1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl,1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl,3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl,2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl,1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl,4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl,3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl,1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl,1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl,1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl,2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl,3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl,1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl,2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl,1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl,1-ethyl-2-methyl-2-propenyl and the like.

The term “fluorinated alkenyl” as used herein refers to unsaturatedstraight-chain or branched hydrocarbon radicals having 2 to 3(“fluorinated C₂-C₃-alkenyl”), 2 to 4 (“fluorinated C₂-C₄-alkenyl”) or 2to 6 (“fluorinated C₂-C₆-alkenyl”) carbon atoms and a double bond in anyposition (as mentioned above), where some or all of the hydrogen atomsin these groups are replaced by fluorine atoms, such as, fluorovinyl,fluoroallyl and the like.

The term “alkynyl” as used herein refers to straight-chain or branchedhydrocarbon groups having 2 to 3 (“C₂-C₃-alkynyl”), 2 to 4(“C₂-C₄-alkynyl”) or 2 to 6 (“C₂-C₆-alkynyl”) carbon atoms and one ortwo triple bonds in any position, such as C₂-C₃-alkynyl, such asethynyl, 1-propynyl or 2-propynyl; C₂-C₄-alkynyl, such as ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-methyl-2-propynyl and the like, and C₂-C₆-alkynyl, such as ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl,3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl,1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl,1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl,2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl,3-methyl-4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl,1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl,2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl,1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl andthe like.

The term “fluorinated alkynyl” as used herein refers to unsaturatedstraight-chain or branched hydrocarbon radicals having 2 to 3(“fluorinated C₂-C₃-alkynyl”), 3 to 4 (“fluorinated C₃-C₄-alkynyl”) or 2to 6 (“fluorinated C₂-C₆-alkynyl”) carbon atoms and one or two triplebonds in any position (as mentioned above), where some or all of thehydrogen atoms in these groups are replaced by fluorine atoms.

The term “cycloalkyl” as used herein refers to monocyclic saturatedhydrocarbon radicals having 3 to 8 (“C₃-C₈-cycloalkyl”), in particular 3to 6 carbon atoms (“C₃-C₆-cycloalkyl”) or 3 to 5 carbon atoms(“C₃-C₅-cycloalkyl”) or 3 or 4 carbon atoms (“C₃-C₄-cycloalkyl”).Examples for C₃-C₄-cycloalkyl are cyclopropyl and cyclobutyl. Examplesof C₃-C₅-cycloalkyl are cyclopropyl, cyclobutyl and cyclopentyl.Examples of C₃-C₆-cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl. Examples of C₃-C₈-cycloalkyl are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term “fluorinated cycloalkyl” as used herein refers to monocyclicsaturated hydrocarbon groups having 3 to 8 (“C₃-C₈-halocycloalkyl”) orpreferably 3 to 6 (“C₃-C₆-halocycloalkyl”) or 3 to 5(“C₃-C₅-halocycloalkyl”) carbon ring members (as mentioned above) inwhich some or all of the hydrogen atoms are replaced by fluorine atoms.Examples include 1-fluorocyclopropyl, 2-fluorocyclopropyl, (S)- and(R)-2,2-difluorocyclopropyl, 1,2-difluorocyclopropyl,2,3-difluorocyclopropyl, pentafluorocyclopropyl, 1-fluorocyclobutyl,2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl,3,3-difluorocyclobutyl, 1,2-difluorocyclobutyl, 1,3-difluorocyclobutyl,2,3-difluorocyclobutyl, 2,4-difluorocyclobutyl,1,2,2-trifluorocyclobutyl, 1-fluorocycloheptyl, 2-fluorocycloheptyl,3-fluorocycloheptyl, 4-fluorocycloheptyl, 1,2-difluorocycloheptyl,1,3-difluorocycloheptyl, 1,4-difluorocycloheptyl,2,2-difluorocycloheptyl, 2,3-difluorocycloheptyl,2,4-difluorocycloheptyl, 2,5-difluorocycloheptyl,2,6-difluorocycloheptyl, 2,7-difluorocycloheptyl,3,3-difluorocycloheptyl, 3,4-difluorocycloheptyl,3,5-difluorocycloheptyl, 3,6-difluorocycloheptyl,4,4-difluorocycloheptyl, 4,5-difluorocycloheptyl, and the like.

The term “cycloalkenyl” as used herein refers to monocyclic partiallyunsaturated, non-aromatic hydrocarbon radicals having 3 to 8(“C₃-C₈-cycloalkenyl”), in particular 5 to 7 carbon atoms(“C₅-C₇-cycloalkenyl”) or 5 or 6 carbon atoms (“C₅-C₆-cycloalkenyl”) andone or more non-cumulative, preferably one, C—C double bonds in thering. Examples for C₅-C₆-cycloalkenyl are cyclopent-1-en-1-yl,cyclopent-1-en-3-yl, cyclopent-1-en-4-yl, cyclopenta-1,3-dien-1-yl,cyclopenta-1,3-dien-2-yl, cyclopenta-1,3-dien-5-yl, cyclohex-1-en-1-yl,cyclohex-1-en-3-yl, cyclohex-1-en-4-yl, cyclohexa-1,3-dien-1-yl,cyclohexa-1,3-dien-2-yl, cyclohexa-1,3-dien-5-yl,cyclohexa-1,4-dien-1-yl and cyclohexa-1,4-dien-3-yl. Examples ofC₅-C₇-cycloalkenyl are, apart those mentioned above, include forC₅-C₆-cycloalkenyl, cyclohept-1-en-1-yl, cyclohept-1-en-3-yl,cyclohept-1-en-4-yl, cyclohept-1-en-5-yl, cyclohepta-1,3-dien-1-yl,cyclohepta-1,3-dien-2-yl, cyclohepta-1,3-dien-5-yl,cyclohepta-1,3-dien-6-yl, cyclohepta-1,4-dien-1-yl,cyclohepta-1,4-dien-2-yl, cyclohepta-1,4-dien-3-yl andcyclohepta-1,4-dien-6-yl. Examples of C₃-C₈-cycloalkenyl are, apartthose mentioned above for C₅-C₆-cycloalkenyl, cycloprop-1-en-1-yl,cycloprop-1-en-3-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,cyclooct-1-en-1-yl, cyclooct-1-en-3-yl, cyclooct-1-en-4-yl,cyclooct-1-en-5-yl, cycloocta-1,3-dien-1-yl, cycloocta-1,3-dien-2-yl,cycloocta-1,3-dien-5-yl, cycloocta-1,3-dien-6-yl,cycloocta-1,4-dien-1-yl, cycloocta-1,4-dien-2-yl,cycloocta-1,4-dien-3-yl, cycloocta-1,4-dien-6-yl,cycloocta-1,4-dien-7-yl, cycloocta-1,5-dien-1-yl, andcycloocta-1,5-dien-3-yl.

The term “fluorinated cycloalkenyl” as used herein refers to monocyclicpartially unsaturated, non-aromatic hydrocarbon radicals having 3 to 8(“fluorinated C₃-C₈-cycloalkenyl”), in particular 5 to 7 carbon atoms(“fluorinated C₅-C₇-cycloalkenyl”) or 5 or 6 carbon atoms (“fluorinatedC₅-C₆-cycloalkenyl”) and one or more non-cumulative, preferably one, C—Cdouble bonds in the ring and in which some or all of the hydrogen atomsare replaced by fluorine atoms.

The term “cycloalkyl-C₁-C₄-alkyl” refers to a C₃-C₈-cycloalkyl group(“C₃-C₈-cycloalkyl-C₁-C₄-alkyl”), preferably a C₃-C₆-cycloalkyl group(“C₃-C₆-cycloalkyl-C₁-C₄-alkyl”) as defined above which is bound to theremainder of the molecule via a C₁-C₄alkyl group, as defined above. Theterm “cycloalkyl-C₁-C₂-alkyl” refers to a C₃-C₈-cycloalkyl group(“C₃-C₈-cycloalkyl-C₁-C₂-alkyl”), preferably a C₃-C₆-cycloalkyl group(“C₃-C₆-cycloalkyl-C₁-C₂-alkyl”) as defined above which is bound to theremainder of the molecule via a C₁-C₂-alkyl group, as defined above.Examples for C₃-C₆-cycloalkyl-C₁-C₂-alkyl are cyclopropylmethyl,cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl,cyclopentylethyl, cyclohexylmethyl and cyclohexylethyl. Examples forC₃-C₆-cycloalkyl-C₁-C₄-alkyl, apart those mentioned forC₃-C₆-cycloalkyl-C₁-C₂-alkyl, are cyclopropylpropyl, cyclopropylbutyl,cyclobutylpropyl, cyclobutylbutyl, cyclopentylpropyl, cyclopentylbutyl,cyclohexylpropyl and cyclohexylbutyl. Examples forC₃-C₈-cycloalkyl-C₁-C₂-alkyl, apart those mentioned forC₃-C₆-cycloalkyl-C₆-cycloalkyl-C₁-C₂-alkyl, are cycloheptylmethyl,cycloheptylethyl, cyclooctylmethyl and cyclooctylethyl. Examples forC₃-C₈-cycloalkyl-C₁-C₄-alkyl, apart those mentioned forC₃-C₈-cycloalkyl-C₁-C₂-alkyl, are cycloheptylpropyl, cycloheptylbutyl,cyclooctylpropyl and cyclooctylbutyl.

The term “fluorinated cycloalkyl-C₁-C₄alkyl” refers to a fluorinatedC₃-C₈-cycloalkyl group (“fluorinated C₃-C₈-cycloalkyl-C₁-C₄-alkyl”),preferably a fluorinated C₃-C₆-cycloalkyl group (“fluorinatedC₃-C₆-cycloalkyl-C₁-C₄-alkyl”) as defined above which is bound to theremainder of the molecule via a C₁-C₄-alkyl group, as defined above. Theterm “fluorinated cycloalkyl-C₁-C₂-alkyl” refers to a fluorinatedC₃-C₈-cycloalkyl group (“fluorinated C₃-C₈-cycloalkyl-C₁-C₂-alkyl”),preferably a fluorinated C₃-C₆-cycloalkyl group (“fluorinatedC₃-C₆-cycloalkyl-C₁-C₂-alkyl”) as defined above which is bound to theremainder of the molecule via a C₁-C₂-alkyl group, as defined above.

The term “C₁-C₂-alkoxy” is a C₁-C₂-alkyl group, as defined above,attached via an oxygen atom. The term “C₁-C₃-alkoxy” is a C₁-C₃-alkylgroup, as defined above, attached via an oxygen atom. The term“C₁-C₄-alkoxy” is a C₁-C₄-alkyl group, as defined above, attached via anoxygen atom. The term “C₁-C₆-alkoxy” is a C₁-C₆-alkyl group, as definedabove, attached via an oxygen atom. C₁-C₂-Alkoxy is methoxy or ethoxy.C₁-C₃-Alkoxy is additionally, for example, n-propoxy and 1-methylethoxy(isopropoxy). C₁-C₄-Alkoxy is additionally, for example, butoxy,1-methylpropoxy (sec-butoxy), 2-methylpropoxy (isobutoxy) or1,1-dimethylethoxy (tert-butoxy). C₁-C₆-Alkoxy is additionally, forexample, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy,1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy,1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy,3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy,1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy,2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy,1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxyor 1-ethyl-2-methylpropoxy. C₁-C₈-Alkoxy is additionally, for example,heptyloxy, octyloxy, 2-ethylhexyloxy and positional isomers thereof.

The term “fluorinated C₁-C₂-alkoxy” is a fluorinated C₁-C₂-alkyl group,as defined above, attached via an oxygen atom. The term “fluorinatedC₁-C₃-alkoxy” is a fluorinated C₁-C₃-alkyl group, as defined above,attached via an oxygen atom. The term “fluorinated C₁-C₆-haloalkoxy” isa fluorinated C₁-C₆-alkyl group, as defined above, attached via anoxygen atom. Fluorinated C₁-C₂-alkoxy is, for example, OCH₂F, OCHF₂,OCF₃, 1-fluoroethoxy, (R)-1-fluoroethoxy, (S)-1-fluoroethoxy,2-fluoroethoxy, 1,1-difluoroethoxy, 1,2-difluoroethoxy,2,2-difluoroethoxy, 1,1,2-trifluoroethoxy, 1,2,2-trifluoroethoxy,2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy or OC₂F₅. FluorinatedC₁-C₃-alkoxy, is additionally, for example, 1-fluoropropoxy,(R)-1-fluoropropoxy, (S)-1-fluoropropoxy, 2-fluoropropoxy,(R)-2-fluoropropoxy, (S)-2-fluoropropoxy, 3-fluoropropoxy,1,1-difluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy,3,3-difluoropropoxy, 3,3,3-trifluoropropoxy,(R)-2-fluoro-1-methylethoxy, (S)-2-fluoro-1-methylethoxy,(R)-2,2-difluoro-1-methylethoxy, (S)-2,2-difluoro-1-methylethoxy,(R)-1,2-difluoro-1-methylethoxy, (S)-1,2-difluoro-1-methylethoxy,(R)-2,2,2-trifluoro-1-methylethoxy, (S)-2,2,2-trifluoro-1-methylethoxy,2-fluoro-1-(fluoromethyl)ethoxy, 1-(difluoromethyl)-2,2-difluoroethoxy,OCH₂—C₂F₅, OCF₂—C₂F₅ or 1-(CH₂F)-2-fluoroethoxy. FluorinatedC₁-C₄-alkoxy is additionally, for example, 1-fluorobutoxy,(R)-1-fluorobutoxy, (S)-1-fluorobutoxy, 2-fluorobutoxy, 3-fluorobutoxy,4-fluorobutoxy, 1,1-difluorobutoxy, 2,2-difluorobutoxy,3,3-difluorobutoxy, 4,4-difluorobutoxy, 4,4,4-trifluorobutoxy ornonafluorobutoxy. Fluorinated C₁-C₆-alkoxy is additionally, for example,5-fluoropentoxy, undecafluoropentoxy, 6-fluorohexoxy ortridecafluorohexoxy.

The term “C₁-C₄-alkoxy-C₁-C₄-alkyl” as used herein, refers to astraight-chain or branched alkyl group having 1 to 4 carbon atoms, asdefined above, where one hydrogen atom is replaced by a C₁-C₄-alkoxygroup, as defined above. The term “C₁-C₆-alkoxy-C₁-C₄-alkyl” as usedherein, refers to a straight-chain or branched alkyl group having 1 to 4carbon atoms, as defined above, where one hydrogen atom is replaced by aC₁-C₆-alkoxy group, as defined above. Examples are methoxymethyl,ethoxymethyl, propoxymethyl, isopropoxymethyl, n-butoxymethyl,sec-butoxymethyl, isobutoxymethyl, tert-butoxymethyl, 1-methoxyethyl,1-ethoxyethyl, 1-propoxyethyl, 1-isopropoxyethyl, 1-n-butoxyethyl,1-sec-butoxyethyl, 1-isobutoxyethyl, 1-tert-butoxyethyl, 2-methoxyethyl,2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 2-n-butoxyethyl,2-sec-butoxyethyl, 2-isobutoxyethyl, 2-tert-butoxyethyl,1-methoxypropyl, 1-ethoxypropyl, 1-propoxypropyl, 1-isopropoxypropyl,1-n-butoxypropyl, 1-sec-butoxypropyl, 1-isobutoxypropyl,1-tert-butoxypropyl, 2-methoxypropyl, 2-ethoxypropyl, 2-propoxypropyl,2-isopropoxypropyl, 2-n-butoxypropyl, 2-sec-butoxypropyl,2-isobutoxypropyl, 2-tert-butoxypropyl, 3-methoxypropyl, 3-ethoxypropyl,3-propoxypropyl, 3-isopropoxypropyl, 3-n-butoxypropyl,3-sec-butoxypropyl, 3-isobutoxypropyl, 3-tert-butoxypropyl and the like.

The term “C₁-C₂-alkoxy-methyl” as used herein, refers to methyl whereone hydrogen atom is replaced by a C₁-C₂-alkoxy group, as defined above.Examples are methoxymethyl and ethoxymethyl. The term“C₁-C₄-alkoxy-methyl” as used herein, refers to methyl where onehydrogen atom is replaced by a C₁-C₄-alkoxy group, as defined above.Examples are methoxymethyl, ethoxymethyl, propoxymethyl,isopropoxymethyl, n-butoxymethyl, sec-butoxymethyl, isobutoxymethyl andtert-butoxymethyl.

The term “fluorinated C₁-C₄-alkoxy-C₁-C₄-alkyl” as used herein, refersto a straight-chain or branched alkyl group having 1 to 4 carbon atoms,as defined above, where one hydrogen atom is replaced by a C₁-C₄-alkoxygroup, as defined above, and wherein at least one, e.g. 1, 2, 3, 4 orall of the remaining hydrogen atoms (either in the alkoxy moiety or inthe alkyl moiety or in both) are replaced by fluorine atoms. The term“fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl” as used herein, refers to astraight-chain or branched alkyl group having 1 to 4 carbon atoms, asdefined above, where one hydrogen atom is replaced by a C₁-C₆-alkoxygroup, as defined above, and wherein at least one, e.g. 1, 2, 3, 4 orall of the remaining hydrogen atoms (either in the alkoxy moiety or inthe alkyl moiety or in both) are replaced by fluorine atoms. Examplesare difluoromethoxymethyl (CHF₂OCH₂), trifluoromethoxymethyl (CF₃OCH₂),1-difluoromethoxyethyl (CHF₂OCH(CH₃)), 1-trifluoromethoxyethyl(CF₃OCH(CH₃)), 2-difluoromethoxyethyl (CHF₂OCH₂CH₂),2-trifluoromethoxyethyl (CF₃OCH₂CH₂), methoxy-difluoromethyl (CH₃OCF₂),2-methoxy-1,1-difluoroethyl (CH₃OCH₂CF₂), 2-methoxy-2,2-difluoroethyl(CH₃OCF₂CH₂), and the like.

The term “hydroxy-C₁-C₄-alkyl” as used herein, refers to astraight-chain or branched alkyl group having 1 to 4 carbon atoms, asdefined above, where one hydrogen atom is replaced by a hydroxyl group.The term “hydroxy-C₁-C₆-alkyl” as used herein, refers to astraight-chain or branched alkyl group having 1 to 6 carbon atoms, asdefined above, where one hydrogen atom is replaced by a hydroxyl group.Examples for hydroxy-C₁-C₄-alkyl include hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl,1-hydroxyprop-2-yl, 2-hydroxyprop-2-yl, 1-hydroxybutyl, 2-hydroxybutyl,3-hydroxybutyl, 4-hydroxybutyl, 1-hydroxybut-2-yl, 2-hydroxybut-2-yl,3-hydroxybut-2-yl, 4-hydroxybut-2-yl, hydroxy-tert-butyl and the like.Examples for hydroxy-C₁-C₆-alkyl are, apart those mentioned forhydroxy-C₁-C₄-alkyl, 1-hydroxypentyl, 2-hydroxypentyl, 3-hydroxypentyl,4-hydroxypentyl, 5-hydroxypentyl, 1-hydroxyhexyl, 2-hydroxyhexyl,3-hydroxyhexyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 6-hydroxyhexyl and thelike.

The term “hydroxy-C₁-C₄-alkoxy” as used herein, refers to a C₁-C₄-alkoxygroup, as defined above, where one hydrogen atom is replaced by ahydroxyl group. The term “hydroxy-C₁-C₆-alkoxy” as used herein, refersto a C₁-C₆-alkoxy group, as defined above, where one hydrogen atom isreplaced by a hydroxyl group. Examples for hydroxy-C₁-C₄-alkoxy includehydroxymethoxy, 1-hydroxyethoxy, 2-hydroxyethoxy, 1-hydroxypropoxy,2-hydroxypropoxy, 3-hydroxypropoxy, 1-hydroxy-2-propoxy,2-hydroxy-2-propoxy, 1-hydroxybutoxy, 2-hydroxybutoxy, 3-hydroxybutoxy,4-hydroxybutoxy, 1-hydroxy-2-butoxy, 2-hydroxy-2-butoxy,3-hydroxy-2-butoxy, 4-hydroxy-2-butoxy, hydroxy-tert-butoxy and thelike. Examples for hydroxy-C₁-C₆-alkoxy include, apart those mentionedfor hydroxy-C₁-C₄-alkoxy, 1-hydroxypentoxy, 2-hydroxypentoxy,3-hydroxypentoxy, 4-hydroxypentoxy, 5-hydroxypentoxy, 1-hydroxyhexoxy,2-hydroxyhexoxy, 3-hydroxyhexoxy, 4-hydroxyhexoxy, 5-hydroxyhexoxy,6-hydroxyhexoxy and the like.

The term “C₁-C₄-alkoxy-C₁-C₄-alkoxy” as used herein, refers to aC₁-C₄-alkoxy group, as defined above, where one hydrogen atom isreplaced by a C₁-C₄-alkoxy group, as defined above. The term“C₁-C₆-alkoxy-C₁-C₄-alkoxy” as used herein, refers to a C₁-C₄-alkoxygroup, as defined above, where one hydrogen atom is replaced by aC₁-C₆-alkoxy group, as defined above. Examples are methoxymethoxy,ethoxymethoxy, propoxymethoxy, isopropoxymethoxy, butoxymethoxy,sec-butoxymethoxy, isobutoxymethoxy, tert-butoxymethoxy,1-methoxyethoxy, 1-ethoxyethoxy, 1-propoxyethoxy, 1-isopropoxyethoxy,1-butoxyethoxy, 1-sec-butoxyethoxy, 1-isobutoxyethoxy,1-tert-butoxyethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-propoxyethoxy,2-isopropoxyethoxy, 2-butoxyethoxy, 2-sec-butoxyethoxy,2-isobutoxyethoxy, 2-tert-butoxyethoxy, 1-methoxypropoxy,1-ethoxypropoxy, 1-propoxypropoxy, 1-isopropoxypropoxy, 1-butoxypropoxy,1-sec-butoxypropoxy, 1-isobutoxypropoxy, 1-tert-butoxypropoxy,2-methoxypropoxy, 2-ethoxypropoxy, 2-propoxypropoxy,2-isopropoxypropoxy, 2-butoxypropoxy, 2-sec-butoxypropoxy,2-isobutoxypropoxy, 2-tert-butoxypropoxy, 3-methoxypropoxy,3-ethoxypropoxy, 3-propoxypropoxy, 3-isopropoxypropoxy, 3-butoxypropoxy,3-sec-butoxypropoxy, 3-isobutoxypropoxy, 3-tert-butoxypropoxy and thelike.

The term “C₁-C₂-alkylthio” is a C₁-C₂-alkyl group, as defined above,attached via a sulfur atom. The term “C₁-C₃-alkylthio” refers to aC₁-C₃-alkyl group, as defined above, attached via a sulfur atom. Theterm “C₁-C₄-alkylthio” is a C₁-C₄-alkyl group, as defined above,attached via a sulfur atom. The term “C₁-C₆-alkylthio” refers to aC₁-C₆-alkyl group, as defined above, attached via a sulfur atom. Theterm “C₁-C₁₀-alkylthio” refers to a C₁-C₁₀-alkyl group, as definedabove, attached via a sulfur atom. C₁-C₂-Alkylthio is methylthio orethylthio. C₁-C₃-Alkylthio is additionally, for example, n-propylthio or1-methylethylthio (isopropylthio). C₁-C₄-Alkylthio is additionally, forexample, butylthio, 1-methylpropylthio (sec-butylthio),2-methylpropylthio (isobutylthio) or 1,1-dimethylethylthio(tert-butylthio). C₁-C₆-Alkylthio is additionally, for example,pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio,1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 2,2-dimethylpropylthio,1-ethylpropylthio, hexylthio, 1-methylpentylthio, 2-methylpentylthio,3-methylpentylthio, 4-methylpentylthio, 1,1-dimethylbutylthio,1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,2-dimethylbutylthio,2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio,2-ethylbutylthio, 1,1,2-trimethylpropylthio, 1,2,2-trimethylpropylthio,1-ethyl-1-methylpropylthio or 1-ethyl-2-methylpropylthio.

The term “fluorinated C₁-C₂-alkylthio” refers to a fluorinatedC₁-C₂-alkyl group, as defined above, attached via a sulfur atom. Theterm “fluorinated C₁-C₃-alkylthio” refers to a fluorinated C₁-C₃-alkylgroup, as defined above, attached via a sulfur atom. The term“fluorinated C₁-C₄-alkylthio” refers to a fluorinated C₁-C₄-alkyl group,as defined above, attached via a sulfur atom. The term “fluorinatedC₁-C₆-alkylthio” refers to a fluorinated C₁-C₆-alkyl group, as definedabove, attached via a sulfur atom. Fluorinated C₁-C₂-alkylthio refersto, for example, SCH₂F, SCHF₂, SCF₃, 2-fluoroethylthio,2,2-difluoroethylthio, 2,2,2-trifluoroethylthio, or SC₂F₅. FluorinatedC₁-C₃-alkylthio may additionally, for example, include2-fluoropropylthio, 3-fluoropropylthio, 2,2-difluoropropylthio,2,3-difluoropropylthio, 3,3,3-trifluoropropylthio, SCH₂—C₂F₅, SCF₂—C₂F₅or 1-(CH₂F)-2-fluoroethylthio. Fluorinated C₁-C₄-alkylthio mayadditionally, for example, include 4-fluorobutylthio ornonafluorobutylthio. Fluorinated C₁-C₆-alkylthio is additionally, forexample, 5-fluoropentylthio, undecafluoropentylthio, 6-fluorohexylthioor dodecafluorohexylthio.

The term “C₁-C₂-alkylsulfinyl” refers to a C₁-C₂-alkyl group, as definedabove, attached via a sulfinyl [S(O)] group. The term“C₁-C₄-alkylsulfinyl” is a C₁-C₄-alkyl group, as defined above, attachedvia a sulfinyl [S(O)] group. The term “C₁-C₆-alkylsulfinyl” is aC₁-C₆-alkyl group, as defined above, attached via a sulfinyl [S(O)]group. C₁-C₂-Alkylsulfinyl is methylsulfinyl or ethylsulfinyl.C₁-C₄-Alkylsulfinyl is additionally, for example, n-propylsulfinyl,1-methylethylsulfinyl (isopropylsulfinyl), butylsulfinyl,1-methylpropylsulfinyl (sec-butylsulfinyl), 2-methylpropylsulfinyl(isobutylsulfinyl) or 1,1-dimethylethylsulfinyl (tert-butylsulfinyl).C₁-C₆-Alkylsulfinyl is additionally, for example, pentylsulfinyl,1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl,1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl,2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl,1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl,4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl,1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl,2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl,3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl,1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl,1-ethyl-1-methylpropylsulfinyl or 1-ethyl-2-methylpropylsulfinyl.

The term “fluorinated C₁-C₂-alkylsulfinyl” refers to a fluorinatedC₁-C₂-alkyl group, as defined above, attached via a sulfinyl [S(O)]group. The term “fluorinated C₁-C₃-alkylsulfinyl” refers to afluorinated C₁-C₃-alkyl group, as defined above, attached via a sulfinyl[S(O)] group. The term “fluorinated C₁-C₄-alkylsulfinyl” refers to afluorinated C₁-C₄-alkyl group, as defined above, attached via a sulfinyl[S(O)] group. The term “fluorinated C₁-C₆-alkylsulfinyl” refers to afluorinated C₁-C₆-alkyl group, as defined above, attached via a sulfinyl[S(O)] group. Fluorinated C₁-C₂-alkylsulfinyl is, for example, S(O)CH₂F,S(O)CHF₂, S(O)CF₃, 2-fluoroethylsulfinyl, 2,2-difluoroethylsulfinyl,2,2,2-trifluoroethylsulfinyl, or S(O)C₂F₅. FluorinatedC₁-C₃-alkylsulfinyl may additionally, for example, include2-fluoropropylsulfinyl, 3-fluoropropylsulfinyl,2,2-difluoropropylsulfinyl, 2,3-difluoropropylsulfinyl,3,3,3-trifluoropropylsulfinyl, S(O)CH₂—C₂F₅, S(O)CF₂—C₂F₅ or1-(CH₂F)-2-fluoroethylsulfinyl. Fluorinated C₁-C₄-alkylsulfinyl mayadditionally, for example, include 4-fluorobutylsulfinyl ornonafluorobutylsulfinyl. Fluorinated C₁-C₆-alkylsulfinyl mayadditionally, for example, include 5-fluoropentylsulfinyl,undecafluoropentylsulfinyl, 6-fluorohexylsulfinyl ordodecafluorohexylsulfinyl.

The term “C₁-C₂-alkylsulfonyl” refers to a C₁-C₂-alkyl group, as definedabove, attached via a sulfonyl [S(O)₂] group. The term“C₁-C₄-alkylsulfonyl” refers to a C₁-C₄-alkyl group, as defined above,attached via a sulfonyl [S(O)₂] group. The term “C₁-C₆-alkylsulfonyl” isa C₁-C₆-alkyl group, as defined above, attached via a sulfonyl [S(O)₂]group. C₁-C₂-Alkylsulfonyl refers to a methylsulfonyl or ethylsulfonyl.C₁-C₄-Alkylsulfonyl is additionally, for example, n-propylsulfonyl,1-methylethylsulfonyl (isopropylsulfonyl), butylsulfonyl,1-methylpropylsulfonyl (sec-butylsulfonyl), 2-methylpropylsulfonyl(isobutylsulfonyl) or 1,1-dimethylethylsulfonyl (tert-butylsulfonyl).C₁-C₆-Alkylsulfonyl is additionally, for example, pentylsulfonyl,1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl,1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl,2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl,1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl,4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl,1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl,2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl,3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl,1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl,1-ethyl-1-methylpropylsulfonyl or 1-ethyl-2-methylpropylsulfonyl.

The term “fluorinated C₁-C₂-alkylsulfonyl” refers to a fluorinatedC₁-C₂-alkyl group, as defined above, attached via a sulfonyl [S(O)₂]group. The term “fluorinated C₁-C₃-alkylsulfonyl” refers to afluorinated C₁-C₃-alkyl group, as defined above, attached via a sulfonyl[S(O)₂] group. The term “fluorinated C₁-C₄-alkylsulfonyl” refers to afluorinated C₁-C₄-alkyl group, as defined above, attached via a sulfonyl[S(O)₂] group. The term “fluorinated C₁-C₆-alkylsulfonyl” refers to afluorinated C₁-C₆-alkyl group, as defined above, attached via a sulfonyl[S(O)₂] group. Fluorinated C₁-C₂-alkylsulfonyl is, for example,S(O)₂CH₂F, S(O)₂CHF₂, S(O)₂CF₃, 2-fluoroethylsulfonyl,2,2-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, S(O)₂C₂F₅.Fluorinated C₁-C₃-alkylsulfonyl is additionally, for example,2-fluoropropylsulfonyl, 3-fluoropropylsulfonyl,2,2-difluoropropylsulfonyl, 2,3-difluoropropylsulfonyl,3,3,3-trifluoropropylsulfonyl, S(O)₂CH₂—C₂F₅, S(O)₂CF₂—C₂F₅ or1-(CH₂F)-2-fluoroethylsulfonyl. Fluorinated C₁-C₄-alkylsulfonyl isadditionally, for example, 4-fluorobutylsulfonyl ornonafluorobutylsulfonyl. Fluorinated C₁-C₆-alkylsulfonyl isadditionally, for example, 5-fluoropentylsulfonyl,undecafluoropentylsulfonyl, 6-fluorohexylsulfonyl ordodecafluorohexylsulfonyl.

C₁-C₄-Alkylcarbonyl refers to a straight-chain or branched alkyl grouphaving from 1 to 4 carbon atoms), which is bound to the remainder of themolecule via a carbonyl group (CO), such as in acetyl, propionyl,isopropylcarbonyl, butylcarbonyl, sec-butylcarbonyl, isobutylcarbonyl,and tert-butylcarbonyl. C₁-C₆-Alkylcarbonyl is a straight-chain orbranched alkyl group having from 1 to 6 carbon atoms, which is bound tothe remainder of the molecule via a carbonyl group (CO). Examplesinclude, apart those listed above for C₁-C₄-alkylcarbonylpentylcarbonyl,hexylcarbonyl and the constitutional isomers thereof.

Fluorinated C₁-C₄-alkylcarbonyl refers to a straight-chain or branchedfluorinated alkyl group having from 1 to 4 carbon atoms as definedabove, which is bound to the remainder of the molecule via a carbonylgroup (CO). Fluorinated C₁-C₆-alkylcarbonyl is a straight-chain orbranched fluorinated alkyl group having from 1 to 6 carbon atoms asdefined above, which is bound to the remainder of the molecule via acarbonyl group (CO). Examples include trifluoromethylcarbonyl,2,2,2-trifluoroethylcarbonyl and the like.

C₃-C₆-cycloalkylcarbonyl relates to a C₃-C₆-cycloalkyl group as definedabove which is bound to the remainder of the molecule via a carbonylgroup (CO), such as in cyclopropylcarbonyl, cyclobutylcarbonyl,cyclopentylcarbonyl and cyclohexylcarbonyl.

C₁-C₆-Alkoxycarbonyl refers to a straight-chain or branched alkoxy grouphaving from 1 to 6, especially 1 to 4 carbon atoms(═C₁-C₄-alkoxycarbonyl), in particular 1 to 3 carbon atoms(═C₁-C₃-alkoxycarbonyl), which is bound to the remainder of the moleculevia a carbonyl group (CO), such as in methoxycarbonyl, ethoxycarbonyl,propyloxycarbonyl, and isopropyloxycarbonyl.

Fluorinated C₁-C₆-alkoxycarbonyl refers to a straight-chain or branchedfluorinated alkoxy group having from 1 to 6, especially 1 to 4 carbonatoms (=fluorinated C₁-C₄-alkoxycarbonyl), in particular 1 to 3 carbonatoms (=fluorinated C₁-C₃-alkoxycarbonyl) as defined above, which isbound to the remainder of the molecule via a carbonyl group (CO).Examples include trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyland the like.

C₁-C₄-Alkylcarbonyloxy refers to a straight-chain or branched alkylgroup having from 1 to 4 carbon atoms, which is bound to the remainderof the molecule via a carbonyloxy group [C(O)—O—], such as inacet(yl)oxy, propionyloxy, isopropylcarbonyloxy, butylcarbonyloxy,sec-butylcarbonyloxy, isobutylcarbonyloxy, and tert-butylcarbonyloxy.C₁-C₆-Alkylcarbonyloxy is a straight-chain or branched alkyl grouphaving from 1 to 6 carbon atoms, which is bound to the remainder of themolecule via a carbonyloxy group [C(O—O—]. Examples include, apart thoselisted above for C₁-C₄-alkylcarbonyloxy, pentylcarbonyloxy,hexylcarbonyloxy and the constitutional isomers thereof.

Fluorinated C₁-C₄-alkylcarbonyloxy refers to a straight-chain orbranched fluorinated alkyl group having from 1 to 4 carbon atoms asdefined above, which is bound to the remainder of the molecule via acarbonyloxy group [C(O)—O—]. Fluorinated C₁-C₆-alkylcarbonyloxy is astraight-chain or branched fluorinated alkyl group having from 1 to 6carbon atoms as defined above, which is bound to the remainder of themolecule via a carbonyloxy group [C(O)—O—]. Examples includetrifluoromethylcarbonyloxy, 2,2,2-trifluoroethylcarbonyloxy and thelike.

Phenyl-C₁-C₂-alkyl is a phenyl group bound to the remainder of themolecule via a C₁-C₂-alkyl group. Examples are benzyl, 1-phenylethyl and2-phenylethyl (phenethyl).

The term “3-, 4-, 5-, 6-, 7- or 8-membered saturated, partiallyunsaturated or maximally unsaturated heterocyclic ring containing 1, 2,3 or 4 heteroatoms or heteroatom groups independently selected from N,O, S, NO, SO and SO₂ and optionally also 1 or 2 C═O and/or C═S groups asring members” denotes a 3-, 4-, 5-, 6-, 7- or 8-membered, preferably a3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or maximumunsaturated heteromonocyclic ring containing 1, 2, 3 or 4 (preferably 1,2 or 3) heteroatoms or heteroatom groups selected from N, O, S, SO andSO₂ and optionally also 1 or 2 C═O and/or C═S groups as ring members.

Unsaturated rings contain at least one C—C and/or C—N and/or N—N doublebond(s). Maximally unsaturated rings contain as many conjugated C—Cand/or C—N and/or N—N double bonds as allowed by the ring size.Maximally unsaturated 5- or 6-membered heterocyclic rings are aromatic.7- and 8-membered rings cannot be aromatic. They are homoaromatic(7-membered ring, 3 double bonds) or have 4 double bonds (8-memberedring). Partially unsaturated rings contain less than the maximum numberof C—C and/or C—N and/or N—N double bond(s) allowed by the ring size.The heterocyclic ring may be attached to the remainder of the moleculevia a carbon ring member or via a nitrogen ring member. As a matter ofcourse, the heterocyclic ring contains at least one carbon ring atom. Ifthe ring contains more than one O ring atom, these are not adjacent.

In heterocyclic rings containing N as a ring member this nitrogen atommay either be present as tertiary N formally bound by a double and asingle bond (like in pyridyl) or may be present as secondary NH (if N isnot part of a ring double bond). In case that N is actually present asNH, and the ring is substituted, the substituent may either be bound toa carbon ring atom or to such a secondary nitrogen ring atom. In casethat N is actually present as NH, the ring may either be bound to theremainder of the molecule via a carbon ring atom or such a secondarynitrogen ring atom.

Examples of a 3-, 4-, 5-, 6- or 7-membered saturated heterocyclic ringinclude: Oxiranyl, thiiranyl, aziridinyl, oxetanyl, thietanyl,azetidinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,tetrahydrofuran-2-on-3-yl, tetrahydrofuran-2-on-4-yl,tetrahydrofuran-2-on-5-yl, tetrahydrofuran-2-thion-3-yl,tetrahydrofuran-2-thion-4-yl, tetrahydrofuran-2-thion-5-yl,tetrahydrothien-2-yl, tetrahydrothien-3-yl, tetrahydrothien-2-on-3-yl,tetrahydrothien-2-on-4-yl, tetrahydrothien-2-on-5-yl,tetrahydrothien-2-thion-3-yl, tetrahydrothien-2-thion-4-yl,tetrahydrothien-2-thion-5-yl, pyrrolidin-1-yl, pyrrolidine-2-on-1-yl,pyrrolidine-2,5-dion-1-yl, pyrrolidine-2-thion-1-yl, pyrrolidin-2-yl,pyrrolidin-3-yl, pyrrolidine-2-on-3-yl, pyrrolidine-2-on-4-yl,pyrrolidine-2-on-5-yl, pyrrolidine-2,5-dion-3-yl,pyrrolidine-2-thion-3-yl, pyrrolidine-2-thion-4-yl,pyrrolidine-2-thion-5-yl, pyrazolidin-1-yl, pyrazolidin-3-yl,pyrazolidin-4-yl, pyrazolidin-5-yl, imidazolidin-1-yl,imidazolidin-2-on-1-yl, imidazolidin-2-thion-1-yl, imidazolidin-2-yl,imidazolidin-4-yl, imidazolidin-2-on-4-yl, imidazolidin-2-thion-4-yl,oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl, oxazolidin-5-yl,isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl,isoxazolidin-5-yl, thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl,thiazolidin-5-yl, isothiazolidin-2-yl, isothiazolidin-3-yl,isothiazolidin-4-yl, isothiazolidin-5-yl, 1,2,4-oxadiazolidin-3-yl,1,2,4-oxadiazolidin-5-yl, 1,2,4-thiadiazolidin-3-yl,1,2,4-thiadiazolidin-5-yl, 1,2,4-triazolidin-3-yl,1,3,4-oxadiazolidin-2-yl, 1,3,4-thiadiazolidin-2-yl,1,3,4-triazolidin-1-yl, 1,3,4-triazolidin-2-yl, 2-tetrahydropyranyl,4-tetrahydropyranyl, 1,3-dioxan-5-yl, 1,4-dioxan-2-yl, piperidin-1-yl,piperidin-2-on-1-yl, piperidin-2,5-dion-1-yl, piperidine-2-thion-1-yl,piperidin-2-yl, piperidin-3-yl, piperidin-2-on-3-yl,piperidin-2,5-dion-3-yl, piperidin-2-thion-3-yl, piperidin-4-yl,hexahydropyridazin-3-yl, hexahydropyridazin-4-yl,hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl,hexahydropyrimidin-5-yl, piperazin-1-yl, piperazin-2-yl,1,3,5-hexahydrotriazin-1-yl, 1,3,5-hexahydrotriazin-2-yl and1,2,4-hexahydrotriazin-3-yl, morpholin-2-yl, morpholin-3-yl,morpholin-4-yl, thiomorpholin-2-yl, thiomorpholin-3-yl,thiomorpholin-4-yl, 1-oxothiomorpholin-2-yl, 1-oxothiomorpholin-3-yl,1-oxothiomorpholin-4-yl, 1,1-dioxothiomorpholin-2-yl,1,1-dioxothiomorpholin-3-yl, 1,1-dioxothiomorpholin-4-yl, azepan-1-,-2-, -3- or -4-yl, oxepan-2-, -3-, -4- or -5-yl,hexahydro-1,3-diazepinyl, hexahydro-1,4-diazepinyl,hexahydro-1,3-oxazepinyl, hexahydro-1,4-oxazepinyl,hexahydro-1,3-dioxepinyl, hexahydro-1,4-dioxepinyl and the like.

Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered saturated heterocyclicring further include oxocane, thiocane, azocane, [1,3]diazocane,[1,4]diazocane, [1,5]diazocane, [1,5]oxazocane and the like.

Examples of a 3-, 4-, 5-, 6- or 7-membered partially unsaturatedheterocyclic ring include: 2,3-dihydrofur-2-yl, 2,3-dihydrofur-3-yl,2,4-dihydrofur-2-yl, 2,4-dihydrofur-3-yl, 2,3-dihydrothien-2-yl,2,3-dihydrothien-3-yl, 2,4-dihydrothien-2-yl, 2,4-dihydrothien-3-yl,2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl,2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl,2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl,2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl,2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl,2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl,2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl,2,3-dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl,2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl,2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-1-yl,3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl,3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-1-yl,4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl,4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl,2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl,3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3,4-dihydrooxazol-5-yl,3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl,2-, 3-, 4-, 5- or 6-di- or tetrahydropyridinyl, 3-di- ortetrahydropyridazinyl, 4-di- or tetrahydropyridazinyl, 2-di- ortetrahydropyrimidinyl, 4-di- or tetrahydropyrimidinyl, 5-di- ortetrahydropyrimidinyl, di- or tetrahydropyrazinyl, 1,3,5-di- ortetrahydrotriazin-2-yl, 1,2,4-di- or tetrahydrotriazin-3-yl,2,3,4,5-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl,3,4,5,6-tetrahydro[2H]azepin-2-, -3-, -4-, -5-, -6- or -7-yl,2,3,4,7-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl,2,3,6,7-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl,tetrahydrooxepinyl, such as 2,3,4,5-tetrahydro[1H]oxepin-2-, -3-, -4-,-5-, -6- or -7-yl, 2,3,4,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6-or -7-yl, 2,3,6,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6- or -7-yl,tetrahydro-1,3-diazepinyl, tetrahydro-1,4-diazepinyl,tetrahydro-1,3-oxazepinyl, tetrahydro-1,4-oxazepinyl,tetrahydro-1,3-dioxepinyl and tetrahydro-1,4-dioxepinyl.

Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered partially unsaturatedheterocyclic ring further include 1,2,3,4,5,6-hexahydroazocine,2,3,4,5,6,7-hexahydroazocine, 1,2,3,4,5,8-hexahydroazocine,1,2,3,4,7,8-hexahydroazocine,1,2,3,4,5,6-hexahydro-[1,5]diazocine,1,2,3,4,7,8-hexahydro-[1,5]diazocineand the like.

Examples of a 3-, 4-, 5-, 6- or 7-membered maximally unsaturated(including aromatic) heterocyclic ring include 5- or 6-memberedheteroaromatic rings, such as 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 1-imidazolyl, 2-imidazolyl,4-imidazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 2-pyridinyl,3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl,1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl and 2-pyrazinyl, and also homoaromaticradicals, such as 1H-azepine, 1H-[1,3]-diazepine and 1H-[1,4]-diazepine.

Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered maximally unsaturatedheterocyclic ring further include [1,3]diazocine, [1,5]diazocine and[1,5]diazocine.

A 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated ormaximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms orheteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═Oand C═S as ring members is either saturated, partially unsaturated andcarbocyclic (if it contains only C═O and/or C═S as heteroatom group andno further heteroatoms or heteroatom groups) or saturated, partiallyunsaturated or maximally unsaturated heterocyclic. Examples are, inaddition to the heterocyclic rings mentioned above, carbocyclic rings,such as cyclopropanonyl, cyclobutanonyl, cyclopentanonyl,cyclohexanonyl, cyclohexandionyl, cycloheptanonyl, cyclooctanonyl,cyclopropanthionyl, cyclobutanthionyl, cyclopentanthionyl,cyclohexanthionyl, cyclohexandithionyl, cycloheptanthionyl,cyclooctanthionyl, cyclopropenonyl, cyclopentenonyl, cyclohexenonyl andthe like.

The remarks made above and in the following with respect to preferredaspects of the invention, e.g. to preferred meanings of the variablesR¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R^(5a), R^(5b), R⁶, R⁷, R⁸, R⁹,R¹⁰, R^(11a), R^(11b), a and b of compounds I, to preferred compounds Iand to preferred embodiments of the method or the use according to theinvention, apply in each case on their own or in particular tocombinations thereof.

In a preferred embodiment, R¹ is selected from hydrogen and C₁-C₆-alkyl,in particular from hydrogen and methyl, and is specifically hydrogen.

In a preferred embodiment, R² is selected from cyano, nitro,C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl andfluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, more preferably from C₁-C₆-alkyl,fluorinated C₁-C₆-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl and fluorinatedC₁-C₄-alkoxy-C₁-C₄-alkyl, even more preferably from C₁-C₆-alkyl andfluorinated C₁-C₆-alkyl, in particular from methyl, ethyl, propyl,isopropyl and CF₃, more particularly from methyl, ethyl and CF₃, and isspecifically methyl or CF₃.

In a preferred embodiment, R^(3a) and R^(3b), independently of eachother, are selected from hydrogen, cyano, nitro, C₁-C₆-alkyl andfluorinated C₁-C₆-alkyl. More preferably, R^(3a) is selected fromhydrogen, cyano, nitro, C₁-C₆-alkyl and fluorinated C₁-C₆-alkyl, andR^(3b) is hydrogen. Even more preferably, R^(3a) is selected fromhydrogen and methyl and R^(3b) is hydrogen. In particular, both R^(3a)and R^(3b) are hydrogen.

In a preferred embodiment, R^(4a) and R^(4b), independently of eachother, are selected from hydrogen, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl and fluorinated C₁-C₄-alkoxy-C₁-C₄-alkyl, orform together a group ═O, or form together a group —(CH₂)_(m)—, where mis 2, 3 or 4, in particular 2 or 3, especially 2, thus forming togethera spiro-bound ring. More preferably, R^(4a) is selected from hydrogen,C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl andfluorinated C₁-C₄-alkoxy-C₁-C4-alkyl and R^(4b) is hydrogen, or R^(4a)and R^(4b) are methyl, or R^(4a) and R^(4b) form together a group—(CH₂)_(m)—, where m is 2, 3 or 4, in particular 2 or 3, especially 2,thus forming together a spiro-bound ring. In a particular embodiment,they are hydrogen.

In a preferred embodiment, R^(5a) is selected from hydrogen, halogen,C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl and C₁-C₆-alkoxy-C₁-C₄-alkyl andR^(5b) is hydrogen. In particular, R^(5a) is hydrogen or methyl,specifically hydrogen, and R^(5b) is hydrogen.

Preferably, each R⁸ as a substituent on R⁶ is independently selectedfrom the group consisting of halogen, C₁-C₆-alkoxy and fluorinatedC₁-C₆-alkoxy. In particular, R⁸ is halogen, especially fluorine.

R⁶ is thus preferably C₁-C₄-haloalkyl, more preferably fluorinatedC₁-C₄-alkyl, in particular fluorinated C₁-C₂-alkyl, such as CH₂F, CHF₂,CF₃ and CH₂CF₃, and specifically fluorinated methyl; very specificallyCHF₂ or CF₃.

Alternatively, R⁶ is preferably selected from C₁-C₆-alkoxy-C₁-C₄-alkyland fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, and is in particularfluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl. In another particular embodiment,R⁶ is C₁-C₆-alkoxy-C₁-C₄-alkyl, specifically C₁-C₄-alkoxy-methyl andvery specifically C₁-C₂-alkoxy-methyl.

In another embodiment, R⁶ is C₁-C₄-alkyl which carries a hydroxylsubstituent.

Among C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, fluorinatedC₁-C₆-alkoxy-C₁-C₄-alkyl and fluorinated C₁-C₄-alkoxy-C₁-C₄-alkylradicals R², R^(4a), R^(4b), R^(5a) and R⁶ preference is given toCH₂OCH₃, CH₂CH₂OCH₃, CH₂OCH₂CH₃, CH₂CH₂OCH₂CH₃, CH₂OCF₃, CH₂CH₂OCF₃,CH₂OCHF₂ and CH₂CH₂OCHF₂.

In a preferred embodiment, each R⁷ is independently selected from thegroup consisting of halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl,fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl,C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinatedC₃-C₈-cycloalkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy. Morepreferably, each R⁷ is independently selected from halogen, C₁-C₄-alkyl,fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy and fluorinated C₁-C₄-alkoxy, andis in particular fluorine.

In a preferred embodiment, a is 0 or 1. If a is 1, R² is preferablybound in β-position to the nitrogen ring atom carrying R¹.

In a preferred embodiment, b is 0 or 1 and specifically 0.

If not specified otherwise in a specific context, R⁹, R¹⁰, R^(11a) andR^(11b) have following preferred meanings:

Preferably each R⁹ is independently selected from the group consistingof hydrogen, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,C₁-C₆-hydroxyalkyl, C₃-C₆-cycloalkyl, fluorinated C₃-C₆-cycloalkyl,C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, and —NR^(11a)R^(11b), whereR^(11a) and R^(11b) have one of the above general or, in particular, oneof the below preferred meanings. In particular, each R⁹ is independentlyselected from the group consisting of hydrogen, C₁-C₄-alkyl, fluorinatedC₁-C₂-alkyl, C₁-C₄-hydroxyalkyl, C₁-C₄-alkoxy, fluorinated C₁-C₂-alkoxy,and —NR^(11a)R^(11b), where R^(11a) and R_(11b) have one of the abovegeneral or, in particular, one of the below preferred meanings.

Preferably, each R¹⁰ is independently selected from the group consistingof halogen, cyano, C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxyand fluorinated C₁-C₄-alkoxy, more preferably from F, Cl, cyano, CH₃,CF₃, OCH₃ and OCF₃, and in particular from F, CH₃, CF₃, OCH₃ and OCF₃.

Preferably, R^(11a) and R^(11b), independently of each other andindependently of each occurrence, are selected from the group consistingof hydrogen, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkylcarbonyland fluorinated C₁-C₆-alkylcarbonyl.

In a particular embodiment, the compounds of the invention are compoundsof formula I.1

wherein R², R⁶, R⁷ and b have one of the above general or, inparticular, one of the above preferred meanings, and a is 0 or 1.

In a more particular embodiment, the compounds of the invention arecompounds of formula I.1.1

wherein

-   -   R^(7a) is H, Cl, F or methyl, in particular H or F, specifically        H;    -   a is 0 or 1; and    -   R², R⁶, R⁷ and b have one of the above general or, in        particular, one of the above preferred meanings.

In compounds I.1.1 (b-1) is preferably 0.

In compounds I.1 and I.1.1 R² is specifically methyl.

Examples of preferred compounds are compounds of the following formulaeIa.1 to Ia.36, where the variables have one of the general or preferredmeanings given above. Examples of preferred compounds are the individualcompounds compiled in the tables 1 to 9360 below. Moreover, the meaningsmentioned below for the individual variables in the tables are per se,independently of the combination in which they are mentioned, aparticularly preferred embodiment of the substituents in question.

Table 1

-   Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶    is CH₂F and the combination of R^(5a), R^(5b) and R^(7a) for a    compound corresponds in each case to one row of Table A.

Table 2

-   Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶    is CHF₂ and the combination of R^(5a), R^(5b) and R^(7a) for a    compound corresponds in each case to one row of Table A.

Table 3

-   Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶    is CF₃ and the combination of R^(5a), R^(5b) and R^(7a) for a    compound corresponds in each case to one row of Table A.

Table 4

-   Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶    is CH₂CHF₂ and the combination of R^(5a), R^(5b) and R^(7a) for a    compound corresponds in each case to one row of Table A.

Table 5

-   Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶    is CH₂CF₃ and the combination of R^(5a), R^(5b) and R^(7a) for a    compound corresponds in each case to one row of Table A.

Table 6

-   Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶    is CF₂CH₃ and the combination of R^(5a), R^(5b) and R^(7a) for a    compound corresponds in each case to one row of Table A.

Table 7

-   Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶    is CF₂CHF₂ and the combination of R^(5a), R^(5b) and R^(7a) for a    compound corresponds in each case to one row of Table A.

Table 8

-   Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶    is CF₂CF₃ and the combination of R^(5a), R^(5b) and R^(7a) for a    compound corresponds in each case to one row of Table A.

Table 9

-   Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶    is CH₂OH and the combination of R^(5a), R^(5b) and R^(7a) for a    compound corresponds in each case to one row of Table A.

Table 10

-   Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶    is CF₂OH and the combination of R^(5a), R^(5b) and R^(7a) for a    compound corresponds in each case to one row of Table A.

Table 11

-   Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶    is CH₂OCH₃ and the combination of R^(5a), R^(5b) and R^(7a) for a    compound corresponds in each case to one row of Table A.

Table 12

-   Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶    is CH₂OCH₂CH₃ and the combination of R^(5a), R^(5b) and R^(7a) for a    compound corresponds in each case to one row of Table A.

Table 13

-   Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶    is CH₂CH₂OCH₃ and the combination of R^(5a), R^(5b) and R^(7a) for a    compound corresponds in each case to one row of Table A.

Table 14

-   Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶    is CH₂CH₂OCH₂CH₃ and the combination of R^(5a), R^(5b) and R^(7a)    for a compound corresponds in each case to one row of Table A.

Table 15

-   Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶    is CH₂OCHF₂ and the combination of R^(5a), R^(5b) and R^(7a) for a    compound corresponds in each case to one row of Table A.

Table 16

-   Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶    is CH₂OCF₃ and the combination of R^(5a), R^(5b) and R^(7a) for a    compound corresponds in each case to one row of Table A.

Table 17

-   Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶    is CH₂CH₂OCHF₂ and the combination of R^(5a), R^(5b) and R^(7a) for    a compound corresponds in each case to one row of Table A.

Table 18

-   Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶    is CH₂CH₂OCF₃ and the combination of R^(5a), R^(5b) and R^(7a) for a    compound corresponds in each ease to one row of Table A.

Table 19

-   Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶    is CH₂CH₂OCH₂CHF₂ and the combination of R^(5a), R^(5b) and R^(7a)    for a compound corresponds in each case to one row of Table A.

Table 20

-   Compounds of the formula Ia.1 in which R^(4a) is H, R^(4b) is H, R⁶    is CH₂CH₂OCH₂CF₃ and the combination of R^(5a), R^(5b) and R^(7a)    for a compound corresponds in each case to one row of Table A.

Tables 21 to 40

-   Compounds of the formula Ia.1 in which R^(4a) is methyl, R^(4b) is    H, R⁶ is as defined in tables 1 to 20 and the combination of R^(5a),    R^(5b) and R^(7a) for a compound corresponds in each case to one row    of Table A.

Tables 41 to 60

-   Compounds of the formula Ia.1 in which R^(4a) is ethyl, R^(4b) is H,    R⁶ is as defined in tables 1 to 20 and the combination of R^(5a),    R^(5b) and R^(7a) for a compound corresponds in each case to one row    of Table A.

Tables 61 to 80

-   Compounds of the formula Ia.1 in which R^(4a) is CH₂OCH₃, R^(4b) is    H, R⁶ is as defined in tables 1 to 20 and the combination of R^(5a),    R^(5b) and R^(7a) for a compound corresponds in each case to one row    of Table A.

Tables 81 to 100

-   Compounds of the formula Ia.1 in which R^(4a) is CH₂OCH₂CH₃, R^(4b)    is H, R⁶ is as defined in tables 1 to 20 and the combination of    R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to    one row of Table A.

Tables 101 to 120

-   Compounds of the formula Ia.1 in which R^(4a) is CH₂CH₂OCH₃, R^(4b)    is H, R⁶ is as defined in tables 1 to 20 and the combination of    R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to    one row of Table A.

Tables 121 to 140

-   Compounds of the formula Ia.1 in which R^(4a) is CH₂CH₂OCH₂CH₃,    R^(4b) is H, R⁶ is as defined in tables 1 to 20 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 141 to 160

-   Compounds of the formula Ia.1 in which R^(4a) is CH₂OCHF₂, R^(4b) is    H, R⁶ is as defined in tables 1 to 20 and the combination of R^(5a),    R^(5b) and R^(7a) for a compound corresponds in each case to one row    of Table A.

Tables 161 to 180

-   Compounds of the formula Ia.1 in which R^(4a) is CH₂OCF₃, R^(4b) is    H, R⁶ is as defined in tables 1 to 20 and the combination of R^(5a),    R^(5b) and R^(7a) for a compound corresponds in each case to one row    of Table A.

Tables 181 to 200

-   Compounds of the formula Ia.1 in which R^(4a) is CH₂CH₂OCHF₂, R^(4b)    is H, R⁶ is as defined in tables 1 to 20 and the combination of    R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to    one row of Table A.

Tables 201 to 220

-   Compounds of the formula Ia.1 in which R^(4a) is CH₂CH₂OCF₃, R^(4b)    is H, R⁶ is as defined in tables 1 to 20 and the combination of    R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to    one row of Table A.

Tables 221 to 240

-   Compounds of the formula Ia.1 in which R^(4a) is methyl, R^(4b) is    methyl, R⁶ is as defined in tables 1 to 20 and the combination of    R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case to    one row of Table A.

Tables 241 to 260

-   Compounds of the formula Ia.1 in which R^(4a) and R^(4b) form    together —CH₂—CH₂—, R⁶ is as defined in tables 1 to 20 and the    combination of R^(5a), R^(5b) and R^(7a) for a compound corresponds    in each case to one row of Table A.

Tables 261 to 520

-   Compounds of the formula Ia.2 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 521 to 780

-   Compounds of the formula Ia.3 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 781 to 1040

-   Compounds of the formula Ia.4 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 1041 to 1300

-   Compounds of the formula Ia.5 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 1301 to 1560

-   Compounds of the formula Ia.6 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 1561 to 1820

-   Compounds of the formula Ia.7 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 1821 to 2080

-   Compounds of the formula Ia.8 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 2081 to 2340

-   Compounds of the formula Ia.9 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 2341 to 2600

-   Compounds of the formula Ia.10 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 2601 to 2860

-   Compounds of the formula Ia.11 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 2861 to 3120

-   Compounds of the formula Ia.12 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 3121 to 3380

-   Compounds of the formula Ia.13 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 3381 to 3641

-   Compounds of the formula Ia.14 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 3641 to 3900

-   Compounds of the formula Ia.15 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 3901 to 4160

-   Compounds of the formula Ia.16 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 4161 to 4420

-   Compounds of the formula Ia.17 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 4421 to 4680

-   Compounds of the formula Ia.18 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 4681 to 4940

-   Compounds of the formula Ia.19 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 4941 to 5200

-   Compounds of the formula Ia.20 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 5201 to 5460

-   Compounds of the formula Ia.21 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 5461 to 5720

-   Compounds of the formula Ia.22 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 5721 to 5980

-   Compounds of the formula Ia.23 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 5981 to 6240

-   Compounds of the formula Ia.24 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 6241 to 6500

-   Compounds of the formula Ia.25 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 6501 to 6760

-   Compounds of the formula Ia.26 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 6761 to 7020

-   Compounds of the formula Ia.27 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 7021 to 7280

-   Compounds of the formula Ia.28 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 7281 to 7540

-   Compounds of the formula Ia.29 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 7541 to 7800

-   Compounds of the formula Ia.30 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 7801 to 8060

-   Compounds of the formula Ia.31 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 8061 to 8320

-   Compounds of the formula Ia.32 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 8321 to 8580

-   Compounds of the formula Ia.33 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 8581 to 8840

-   Compounds of the formula Ia.34 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 8841 to 9100

-   Compounds of the formula Ia.35 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

Tables 9101 to 9360

-   Compounds of the formula Ia.36 in which the combination of R^(4a),    R^(4b) and R⁶ is as defined in tables 1 to 260 and the combination    of R^(5a), R^(5b) and R^(7a) for a compound corresponds in each case    to one row of Table A.

TABLE A No. R^(7a) R^(5a) R^(5b) A-1 H H H A-2 F H H A-3 Cl H H A-4 CH₃H H A-5 CHF₂ H H A-6 CF₃ H H A-7 OCH₃ H H A-8 OCHF₂ H H A-9 OCF₃ H HA-10 cyclopropyl H H A-11 H CH₃ H A-12 F CH₃ H A-13 Cl CH₃ H A-14 CH₃CH₃ H A-15 CHF₂ CH₃ H A-16 CF₃ CH₃ H A-17 OCH₃ CH₃ H A-18 OCHF₂ CH₃ HA-19 OCF₃ CH₃ H A-20 cyclopropyl CH₃ H A-21 H CH₂CH₃ H A-22 F CH₂CH₃ HA-23 Cl CH₂CH₃ H A-24 CH₃ CH₂CH₃ H A-25 CHF₂ CH₂CH₃ H A-26 CF₃ CH₂CH₃ HA-27 OCH₃ CH₂CH₃ H A-28 OCHF₂ CH₂CH₃ H A-29 OCF₃ CH₂CH₃ H A-30cyclopropyl CH₂CH₃ H A-31 H CH₂OCH₃ H A-32 F CH₂OCH₃ H A-33 Cl CH₂OCH₃ HA-34 CH₃ CH₂OCH₃ H A-35 CHF₂ CH₂OCH₃ H A-36 CF₃ CH₂OCH₃ H A-37 OCH₃CH₂OCH₃ H A-38 OCHF₂ CH₂OCH₃ H A-39 OCF₃ CH₂OCH₃ H A-40 cyclopropylCH₂OCH₃ H A-41 H CH₂OCH₂CH₃ H A-42 F CH₂OCH₂CH₃ H A-43 Cl CH₂OCH₂CH₃ HA-44 CH₃ CH₂OCH₂CH₃ H A-45 CHF₂ CH₂OCH₂CH₃ H A-46 CF₃ CH₂OCH₂CH₃ H A-47OCH₃ CH₂OCH₂CH₃ H A-48 OCHF₂ CH₂OCH₂CH₃ H A-49 OCF₃ CH₂OCH₂CH₃ H A-50cyclopropyl CH₂OCH₂CH₃ H A-51 H CH₂CH₂OCH₃ H A-52 F CH₂CH₂OCH₃ H A-53 ClCH₂CH₂OCH₃ H A-54 CH₃ CH₂CH₂OCH₃ H A-55 CHF₂ CH₂CH₂OCH₃ H A-56 CF₃CH₂CH₂OCH₃ H A-57 OCH₃ CH₂CH₂OCH₃ H A-58 OCHF₂ CH₂CH₂OCH₃ H A-59 OCF₃CH₂CH₂OCH₃ H A-60 cyclopropyl CH₂CH₂OCH₃ H A-61 H CH₂CH₂OCH₂CH₃ H A-62 FCH₂CH₂OCH₂CH₃ H A-63 Cl CH₂CH₂OCH₂CH₃ H A-64 CH₃ CH₂CH₂OCH₂CH₃ H A-65CHF₂ CH₂CH₂OCH₂CH₃ H A-66 CF₃ CH₂CH₂OCH₂CH₃ H A-67 OCH₃ CH₂CH₂OCH₂CH₃ HA-68 OCHF₂ CH₂CH₂OCH₂CH₃ H A-69 OCF₃ CH₂CH₂OCH₂CH₃ H A-70 cyclopropylCH₂CH₂OCH₂CH₃ H A-71 H CH₃ CH₃ A-72 F CH₃ CH₃ A-73 Cl CH₃ CH₃ A-74 CH₃CH₃ CH₃ A-75 CHF₂ CH₃ CH₃ A-76 CF₃ CH₃ CH₃ A-77 OCH₃ CH₃ CH₃ A-78 OCHF₂CH₃ CH₃ A-79 OCF₃ CH₃ CH₃ A-80 cyclopropyl CH₃ CH₃ A-81 H CH₂CH₃ CH₃A-82 F CH₂CH₃ CH₃ A-83 Cl CH₂CH₃ CH₃ A-84 CH₃ CH₂CH₃ CH₃ A-85 CHF₂CH₂CH₃ CH₃ A-86 CF₃ CH₂CH₃ CH₃ A-87 OCH₃ CH₂CH₃ CH₃ A-88 OCHF₂ CH₂CH₃CH₃ A-89 OCF₃ CH₂CH₃ CH₃ A-90 cyclopropyl CH₂CH₃ CH₃

Among the above compounds, preference is given to compounds Ia.1 andIa.10.

In a specific embodiment, the invention relates to compounds I selectedfrom the compounds of the examples, either in form of free bases or ofany pharmaceutically acceptable salt thereof or a stereoisomer, theracemate or any mixture of stereoisomers thereof.

The compounds of the present invention can be prepared by using routinetechniques familiar to a skilled person. In particular, the compounds ofthe formula I can be prepared according to the following schemes,wherein the variables, if not stated otherwise, are as defined above.

Compounds of formula I wherein R^(4b) and R^(5b) are H (=compounds I′)can be synthesized as described in scheme 1 below. The readily availablequinoline 1 in which X is a leaving group, such as Cl, Br I or triflate,is reacted with a suitable boron compound of R⁶, such as R⁶-boronic acid(R⁶—B(OH)₂) or the potassium (trifluoro)borate of R⁶ in a Suzukicoupling reaction to 2. The reaction is carried out in the presence of aPd catalyst, such as Pd(OAc)₂, in general in the presence of a phosphineligand (e.g. tricyclohexylphosphine; di(adamantan-1-yl)(butyl)-phosphineetc.), or tetrakis(triphenylphosphine)palladium(0) and the like.Quinoline 2 is then N-alkylated with a suitable protective group, suchas benzyl, e.g. by reaction with benzyl bromide, to 3. Reduction of thequinolinium compound 3 with a suitable reduction agent, such as sodiumborohydride and H₂/Raney nickel, yields the 1,2,3,4-tetrahydroquinoline4, which is then deprotected to 5. Reaction with the 2-halogenoacetamide6, wherein Y is Cl, Br or I, affords the acetamide 7, the keto group ofwhich is reduced with common reduction agents, like borane,borane-tetrahydrofurane-complex, borane-dimethylsulfide-complex orborohydrides such as sodium borohydride or LAH (lithium aluminiumhydride) or DIBAL-H (diisobutyl aluminium hydride), to 8. Cyclizationwith formaldehyde/aldehyde/ketone 9 (C(O)R^(3a)R^(3b)=formaldehyde ifR^(3a) and R^(3b) are hydrogen; another aldehyde if R^(3a) is hydrogenand R^(3b) is (fluorinated) alkyl, hydroxyalkyl, (fluorinated) alkenyl,(fluorinated) alkynyl, (fluorinated) cycloalkyl, phenyl, phenyl-alkyl ora heterocyclic ring; a ketone if R^(3a) and R^(3b) are (fluorinated)alkyl, hydroxyalkyl, (fluorinated) alkenyl, (fluorinated) alkynyl,(fluorinated) cycloalkyl, phenyl, phenyl-alkyl or a heterocyclic ring),generally in the presence of a strong acid, such as trifluoroaceticacid, yields I′.

Alternatively, 2 can be reacted with the 2-halogenoacetamide 6 to 10,which is then reduced to 7.

Compounds of formula I wherein R^(4a), R^(4b) and R^(5b) are H(=compounds II″) can alternatively be synthesized as described in scheme2 below. The boronic acid 11 and the α,β-unsaturated ester 12 arereacted in a 1,4-addition in the presence of a Rhodium catalyst, e.g.[RhOH(COD)]₂ or Rh(acac)(CO)₂, if desired in the presence of a phosphineligand, such as 1,4-bis(diphenylphosphino)butane (dppb), followed bylactam formation. The lactam 13 is then reduced with common reductionagents, like borane, borane-tetrahydrofurane-complex,borane-dimethylsulfide-complex or borohydrides such as sodiumborohydride, to the tetrahydroquinoline 14. Like in the reactionsequence of scheme 1, reaction with the 2-halogenoacetamide 6, wherein Yis Cl, Br or I, affords the acetamide 15, the keto group of which isreduced with common reduction agents, like borane,borane-tetrahydrofurane-complex, borane-dimethylsulfide-complex orborohydrides such as sodium borohydride or LAH (lithium aluminiumhydride) or DIBAL-H (diisobutyl aluminium hydride), to 16. Cyclizationwith formaldehyde/aldehyde/ketone 9, generally in the presence of astrong acid, such as trifluoroacetic acid, yields I″.

For obtaining compounds I wherein R^(4a) and R^(4b) form together ═O,the lactam 13 is not reduced, but is directly reacted with the2-halogenoacetamide 6 to 17, followed by reduction of the CO group inthe amide to 18 and finally cyclization, as shown in scheme 3 below.Alternatively, compounds I′″ can be obtained as described below scheme4.

Compounds of formula I wherein R⁴a, R^(4b) and R^(5b) are H (=compoundsI″) can alternatively be synthesized as described in scheme 4 below. Theprotected tetrahydrobenzodiazepine 19, wherein Z is a hydrogen or ahalogen atom, such as Cl, Br or I and PG is a common protective group,such as a carbamate, especially boc, is acylated with the acrylic acidderivative 20, wherein LG is an appropriate leaving group, such as Cl oran anhydride or a chloroformate, in the presence of a base, such astriethylamine or Hünig's base, in an organic solvent, such as ether ormethylene chloride. Reaction of 21 with a Lewis acid or a Brönstedt acidHA or irradiation with a suitable wavelength commonly derived from amercury lamp in an adequate solvent, such as acetone or toluene, in acommon photoreactor yields cyclization to 22. Reduction of the carbonylgroup with common reduction agents like borohydrides such as sodiumborohydride or borane-tetrahydrofurane-complex yields 23, which isdeprotected using suitable reagents such as strong bases or acids to I″,wherein R^(4a) and R^(4b) and R^(5b) are H. Compounds I″″ wherein R^(4a)and R^(4b) form together ═O can be obtained by skipping the reductionstep to 23 and deprotecting 22.

Alternatively, compound 22 can be directly synthesized by reacting thetetrahydrobenzodiazepine 19, wherein Z is —B(OH)₂ with the acrylic acidderivative 20 in a 1,4-addition in the presence of a Rhodium catalyst,e.g. [RhOH(COD)]₂ or Rh(acac)(CO)₂, if desired in the presence of aphosphine ligand, such as 1,4-bis(diphenylphosphino)butane (dppb),followed by lactam formation to 22. This is then further reacted asdescribed above.

If compound 22 is deprotected, this yields compound I′″ as well as othercompounds I in which (R²)_(a) is not necessarily bound to the sameposition as in compounds I′″.

If desired, substituents R¹ different from hydrogen can be introducedfor example via alkylation under typical conditions such as stirring inan appropriate solvent in the presence of an alkylhalide and a base orvia other common substitution reactions, or via reductive aminationusing a suitable aldehyde or ketone in the presence of reduction agent,such as borohydrides, e.g. triacetoxyborohydride, sodiumcyanoborohydride or sodium borohydride. —C(═O)R⁹ as radical R¹ can beintroduced via amidation under typical amidation conditions, e.g. viareaction with a compound X—C(═O)R⁹, where X is OH or a halogen atom,under heating and removal of reaction water or using a coupling reagent,such as DCC (dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide),HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate), HBTU((O-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate), HCTU(1H-benzotriazolium-1-[bis(dimethylamino)methylene]-5-chlorotetrafluoroborate), BOP((benzotriazol-1-yloxy)-tris(dimethylamino)phosphoniumhexafluorophosphate), Py-BOP((benzotriazol-1-yloxy)-tripyrrolidinphosphonium hexafluorophosphate) orPy-BrOP (bromotripyrrolidinphosphonium hexafluorophosphate).

Compounds I wherein R^(5b) is different from H can be prepared, forexample, by reacting compound 22 with a compound LG-R^(5b) in thepresence of a base, wherein LG is an appropriate leaving group, such asCl or Br.

Alternatively to the method depicted in scheme 4, compounds I whereinR^(4a), R^(4b) and R^(5b) are H (=compounds I″) can be synthesized asdescribed in scheme 5 below. Readily available anilines 24 arederivatized with carbonyl moieties 25 by acylation procedures employingappropriate leaving groups LG, such as chlorides or anhydrides, in thepresence of a base such as triethylamine or Hünig's base, in an organicsolvent, such as diethyl ether or methylene chloride to yield 26.Cyclization products 13 are received by irradiation with a suitablewavelength commonly derived from a mercury lamp in an adequate solventsuch as acetone or toluene in a common photoreactor known to thoseskilled in the art. These are further reacted as depicted in schemes 2and 3.

Compounds I wherein R^(4a) and R^(4b) are not H or do not form togethera group ═O can be prepared by standard derivatization methods ofcompounds wherein R^(4a) and R^(4b) form together a group ═O. Forinstance, compounds wherein R^(4a) and R^(4b) form together a group ═Smay be prepared by reaction with a sulfurization agent, such asLawesson's reagent or P₂S₅. Alkyl and related groups as radicals R^(4a)and R^(4b) may be introduced via Grignard reduction. Amino and relatedgroups may be introduced via reductive amination. Hydroxyl group R^(4a)or R^(4b) may be introduced by reducing the carbonyl group. This may bealkylated to yield alkoxy and related groups R^(4a) and R^(4b) orsubstituted by diverse groups.

If not otherwise indicated, the above-described reactions are generallycarried out in a solvent at temperatures between room temperature andthe boiling temperature of the solvent employed. Alternatively, theactivation energy which is required for the reaction can be introducedinto the reaction mixture using microwaves, something which has provedto be of value, in particular, in the case of the reactions catalyzed bytransition metals (with regard to reactions using microwaves, seeTetrahedron 2001, 57, p. 9199 ff. p. 9225 ff. and also, in a generalmanner, “Microwaves in Organic Synthesis”, André Loupy (Ed.), Wiley-VCH2002.

The acid addition salts of compounds I are prepared in a customarymanner by mixing the free base with a corresponding acid, whereappropriate in solution in an organic solvent, for example a loweralcohol, such as methanol, ethanol or propanol, an ether, such as methyltert-butyl ether or diisopropyl ether, a ketone, such as acetone ormethyl ethyl ketone, or an ester, such as ethyl acetate.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that may not be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the preparation methods are within routinetechniques.

Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which maybe found in T. Greene and P. Wuts, Protective Groups in OrganicSynthesis (3^(rd) ed.), John Wiley & Sons, NY (1999), which is hereinincorporated by reference in its entirety. Synthesis of the compounds ofthe invention may be accomplished by methods analogous to thosedescribed in the synthetic schemes described hereinabove and in specificexamples.

Starting materials, if not commercially available, may be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound of the invention isrequired, it may be obtained by carrying out one of the proceduresdescribed herein using an optically active starting material (prepared,for example, by asymmetric induction of a suitable reaction step), or byresolution of a mixture of the stereoisomers of the compound orintermediates using a standard procedure (such as chromatographicseparation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound of the inventionis required, it may be obtained by carrying out one of the aboveprocedures using a pure geometric isomer as a starting material, or byresolution of a mixture of the geometric isomers of the compound orintermediates using a standard procedure such as chromatographicseparation.

The present invention further relates to a pharmaceutical compositioncomprising a therapeutically effective amount of at least one compoundas defined above or an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof, in combination with at leastone pharmaceutically acceptable carrier and/or auxiliary substance.

The present invention further relates to a compound I as defined aboveor an N-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof for use as a medicament.

The present invention also relates to a compound I as defined above oran N-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof for the treatment of disorders which respond tothe modulation of the 5-HT_(2C) receptor.

The present invention also relates to the use of a compound I as definedabove or of an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of disorders which respond to themodulation of the 5-HT_(2C) receptor, and to a method for treatingdisorders which respond to the modulation of the 5-HT_(2C) receptor,which method comprises administering to a subject in need thereof atleast one compound I as defined above or an N-oxide, a tautomeric form,a stereoisomer or a pharmaceutically acceptable salt thereof.

The compounds of the present invention are modulators of the 5-HT_(2C)receptor. Specifically, the compounds of formula I are agonists orpartial agonists of the 5-HT_(2C) receptor. Thus, in a specificembodiment, the invention relates to a compound I as defined above or anN-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof for the treatment of disorders which respond to5-HT_(2C) receptor agonists, further to the use of a compound I asdefined above or of an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of disorders which respond to 5-HT_(2C)receptor agonists, and to a method for treating disorders which respondto 5-HT_(2C) receptor agonists, which method comprises administering toa subject in need thereof at least one compound I as defined above or anN-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof.

Within the meaning of the invention, the term “disorder” denotesdisturbances and/or anomalies which are as a rule regarded as beingpathological conditions or functions and which can manifest themselvesin the form of particular signs, symptoms and/or malfunctions. While thetreatment according to the invention can be directed toward individualdisorders, i.e. anomalies or pathological conditions, it is alsopossible for several anomalies, which may be causatively linked to eachother, to be combined into patterns, i.e. syndromes, which can betreated in accordance with the invention.

In one aspect of the invention, the diseases to be treated are disordersare damage of the central nervous system, disorders of the centralnervous system, eating disorders, ocular hypertension, cardiovasculardisorders, gastrointestinal disorders and diabetes.

Disorders or diseases of the central nervous system are understood asmeaning disorders which affect the spinal cord and, in particular, thebrain. These are, for example, cognitive dysfunction, attention deficitdisorder/hyperactivity syndrome and cognitive deficits related withschizophrenia, attention deficit/hyperactivity syndrome, personalitydisorders, affective disorders, motion or motor disorders, pain,migraine, sleep disorders (including disturbances of the Circadianrhythm), feeding disorders, diseases associated with neurodegeneration,addiction diseases, obesity or psoriasis.

Examples of cognitive dysfunction are deficits in memory, cognition, andlearning, Alzheimer's disease, age-related cognitive decline, and mildcognitive impairment, or any combinations thereof. Examples ofpersonality disorders are schizophrenia and cognitive deficits relatedto schizophrenia. Examples of affective disorders are depression,anxiety, bipolar disorder and obsessive compulsive disorders, or anycombination thereof. Examples of motion or motor disorders areParkinson's disease and epilepsy. Examples of feeding disorders areobesity, bulimia, weight loss and anorexia, especially anorexia nervosa.Examples of diseases associated with neurodegeneration are stroke,spinal or head trauma, and head injuries, such as hydrocephalus.

Pain condition includes nociceptive pain, neuropathic pain or acombination thereof. Such pain conditions or disorders can include, butare not limited to, post-operative pain, osteoarthritis pain, pain dueto inflammation, rheumatoid arthritis pain, musculoskeletal pain, burnpain (including sunburn), ocular pain, the pain associated with dentalconditions (such as dental caries and gingivitis), post-partum pain,bone fracture, herpes, HIV, traumatic nerve injury, stroke,post-ischemia, fibromyalgia, reflex sympathetic dystrophy, complexregional pain syndrome, spinal cord injury, sciatica, phantom limb pain,diabetic neuropathy, hyperalgesia and cancer.

In certain other embodiments, the disease condition is bladderdysfunction, including urinary incontinence.

Diabetes includes diabetes insipidus, diabetes mellitus, type Idiabetes, type II diabetes, type III diabetes, diabetes secondary topancreatic diseases, diabetes related to steroid use, diabetescomplications, hyperglycemia and insulin resistance.

The addiction diseases include psychiatric disorders and behavioraldisturbances which are caused by the abuse of psychotropic substances,such as pharmaceuticals or narcotics, and also other addiction diseases,such as addiction to gaming (impulse control disorders not elsewhereclassified). Examples of addictive substances are: opioids (e.g.morphine, heroin and codeine), cocaine; nicotine; alcohol; substanceswhich interact with the GABA chloride channel complex, sedatives,hypnotics and tranquilizers, for example benzodiazepines; LSD;cannabinoids; psychomotor stimulants, such as3,4-methylenedioxy-N-methylamphetamine (ecstasy); amphetamine andamphetamine-like substances such as methylphenidate, other stimulantsincluding caffeine and nicotine. Addictive substances which comeparticularly into consideration are opioids, cocaine, amphetamine oramphetamine-like substances, nicotine and alcohol. Especially, addictiondisorders include alcohol abuse, cocaine abuse, tobacco abuse andsmoking cessation.

With regard to the treatment of addiction diseases, particularpreference is given to those compounds according to the invention of theformula (I) which themselves do not possess any psychotropic effect.This can also be observed in a test using rats, which, after having beenadministered compounds which can be used in accordance with theinvention, reduce their self administration of psychotropic substances,for example cocaine.

Examples of gastrointestinal disorders are irritable bowel syndrome.

Preferably, the disorders are selected from the group consisting ofbipolar disorder, depression, atypical depression, mood episodes,adjustment disorders, anxiety, panic disorders, post-traumatic syndrome,psychoses, schizophrenia, cognitive deficits of schizophrenia, memoryloss, dementia of aging, Alzheimer's disease, neuropsychiatric symptomsin Alzheimer's disease (e.g. aggression), behavioral disordersassociated with dementia, social phobia, mental disorders in childhood,attention deficit hyperactivity disorder, organic mental disorders,autism, mutism, disruptive behavior disorder, impulse control disorder,borderline personality disorder, obsessive compulsive disorder, migraineand other conditions associated with cephalic pain or other pain, raisedintracranial pressure, seizure disorders, epilepsy, substance usedisorders, alcohol abuse, cocaine abuse, tobacco abuse, smokingcessation, sexual dysfunction/erectile dysfunction in males, sexualdysfunction in females, premenstrual syndrome, late luteal phasesyndrome, chronic fatigue syndrome, sleep disorders, sleep apnoea,chronic fatigue syndrome, psoriasis, Parkinson's disease, psychosis inParkinson's disease, neuropsychiatric symptoms in Parkinson's disease(e.g. aggression), Lewy Body dementia, neuropsychiatric symptoms in LewyBody dementia (e.g. aggression), spinal cord injury, trauma, stroke,pain, bladder dysfunction/urinary incontinence, encephalitis,meningitis, eating disorders, obesity, bulimia, weight loss, anorexianervosa, ocular hypertension, cardiovascular disorders, gastrointestinaldisorders, diabetes insipidus, diabetes mellitus, type I diabetes, typeII diabetes, type III diabetes, diabetes secondary to pancreaticdiseases, diabetes related to steroid use, diabetes complications,hyperglycemia and insulin resistance, and are specificallyschizophrenia, depression, bipolar disorders, obesity, substance usedisorders, neuropsychiatric symptoms in Alzheimer's disease (e.g.aggression) or neuropsychiatric symptoms in Parkinson's disease (e.g.aggression).

The compounds of the invention may be used for a preventive treatment(prophylaxis), in particular as relapse prophylaxis or phaseprophylaxis, but are preferably used for a treatment in its proper sense(i.e. non-prophylactic), i.e. for the treatment of acute or chronicsigns, symptoms and/or malfunctions. The treatment can be orientatedsymptomatically, for example as the suppression of symptoms. It can beeffected over a short period, be orientated over the medium term or canbe a long-term treatment, for example within the context of amaintenance therapy.

In another embodiment, the present invention relates to the use of acompound I as defined above or an N-oxide, a tautomeric form, astereoisomer or a pharmaceutically acceptable salt thereof for preparinga medicament for preventing (the development of) a disease condition asdescribed above and to a method for preventing (the development of) adisease condition as described above comprises administering to thesubject in need of treatment thereof (e.g., a mammal, such as a human) atherapeutically effective amount of a compound I as defined above or anN-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof. As used herein, the term “prevent” a diseasecondition by administration of any of the compounds described hereinmeans that the detectable physical characteristics or symptoms of thedisease or condition do not develop following the administration of thecompound described herein. Alternatively, the method comprisesadministering to the subject a therapeutically effective amount of acompound I as defined above or an N-oxide, a tautomeric form, astereoisomer or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of at least onecognitive enhancing drug.

In yet another embodiment, the present invention relates to the use acompound I as defined above or an N-oxide, a tautomeric form, astereoisomer or a pharmaceutically acceptable salt thereof for preparinga medicament for preventing the progression (e.g., worsening) of adisease condition and to a method for preventing the progression (e.g.,worsening) of a disease condition, which method comprises administeringto the subject in need of treatment thereof (e.g., a mammal, such as ahuman) a therapeutically effective amount of a compound I as definedabove or an N-oxide, a tautomeric form, a stereoisomer or apharmaceutically acceptable salt thereof.

There are several lines of evidence suggesting that 5-HT_(2C) agonistsor partial agonists would have therapeutic use in a variety of diseases,disorders and conditions.

Knockout mice models lacking the 5-HT_(2C) receptor exhibit hyperphagia,obesity and are more prone to seizures and sudden death [Tecott L H, SunL M, Akana S F, Strack A M, Lowenstein D H, Dallman M F, Julius D (1995)Eating disorder and epilepsy in mice lacking 5-HT_(2C) serotoninreceptors. Nature 374:542-546]. They also exhibit compulsive-likebehavior [Chou-Green J M, Holscher T D, Dallman M F, Akana S F (2003).Compulsive behavior in the 5-HT_(2C) receptor knockout mouse. Phys.Behav. 78:641-649], hyperresponsiveness to repeated stress [Chou-Green JM, Holscher T D, Dallman M F, Akana S F (2003). Repeated stress in youngand old 5-HT_(2C) receptor knockout mouse. Phys. Behav. 79:217-226],wakefulness [Frank M G, Stryker M P, Tecott L H (2002). Sleep and sleephomeostasis in mice lacking the 5-HT_(2C) receptor.Neuropsychopharmacology 27:869-873], hyperactivity and drug dependence[Rocha B A, Goulding E H, O'Dell L E, Mead A N, Coufal N G, Parsons L H,Tecott L H (2002). Enhanced locomotor, reinforcing and neurochemicaleffects of cocaine in serotonin 5-hydroxytryptamine 2C receptor mutantmice. J Neurosci. 22:10039-10045].

5-HT_(2C) is unique among other G-protein-coupled receptors (GPCRs) inthat its pre-mRNA is a substrate for base modification via hydrolyticdeamination of adenosines to yield inosines. Five adenosines, locatedwithin a sequence encoding the putative second intracellular domain canbe converted to inosines. This editing can alter the coding potential ofthe triplet codons and allows for the generation of multiple differentreceptor isoforms. The edited receptor isoforms were shown to havereduced ability to interact with G-proteins in the absence of agoniststimulation [Werry, T D, Loiacono R, Sexton P A, Christopoulos A (2008).RNA editing of the serotonin 5-HT_(2C) receptor and its effects on cellsignaling, pharmacology and brain function. Pharmac. Therap. 119:7-23].

Edited 5-HT_(2C) isoforms with reduced function are significantlyexpressed in the brains of depressed suicide victims [Schmauss C (2003)Serotonin 2C receptors: suicide, serotonin, and runaway RNA editing.Neuroscientist 9:237-242. Iwamoto K, Kato T (2003). RNA editing ofserotonin 2C receptor in human postmortem brains of major mentaldisorders. Neurosci. Lett. 346:169-172] and in the learned helplessnessrats (a well established animal model of depression) [Iwamotoa K,Nakatanib N, Bundoa M, Yoshikawab T, Katoa T (2005). Altered RNA editingof serotonin 2C receptor in a rat model of depression. Neurosci. Res.53: 69-76] suggesting a link between 5-HT_(2C) function and depression.There are also implications of edited 5-HT_(2C) isoforms and spatialmemory [Du Y, Stasko M, Costa A C, Davissone M T, Gardiner K J (2007).Editing of the serotonin 2C receptor pre-mRNA Effects of the MorrisWater Maze, Gene 391:186-197]. In addition, fully edited isoforms of thehuman 5-HT_(2C) receptor display a striking reduction in sensitivity tolysergic acid diethylamide (LSD) and to atypical antipsychotic drugsclozapine and loxapine, suggesting a possible role of the receptor inthe etiology and pharmacology of schizophrenia [Niswender C M,Herrick-Davis K, Dilley G E, Meltzer H Y, Overholser J C, Stockmeier CA, Emeson R B, Sanders-Bush E (2001). RNA Editing of the Human Serotonin5-HT_(2C) Receptor: Alterations in Suicide and Implications forSerotonergic Pharmacotherapy. Neuropsychopharm. 24:478-491].

Recently, the availability of potent and selective 5-HT_(2C) receptoragonists made it possible to directly investigate the effects of5-HT_(2C) agonists and their therapeutic potential. Thus recent studiesdemonstrated that selective 5-HT_(2C) agonists resulted in decreasedfood intake and body weight gain in normal and obese rats [Smith B M, etal. (2008). Discovery and structure-activity relationship of(1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin),a selective serotonin 5-HT_(2C) receptor agonist for the treatment ofobesity. J Med Chem 51:305-313. Thomsen W J, Grottick A J, Menzaghi F,Reyes-Saldana H, Espitia S, Yuskin D, Whelan K, Martin M, Morgan M, ChenW, Al-Shama H, Smith B, Chalmers D, Behan D (2008) Lorcaserin, A NovelSelective Human 5-HT_(2C) Agonist: In Vitro and In Vivo PharmacologicalCharacterization. J Pharmacol Exp Ther. 325:577-587. Rosenzweig-LipsonS, Zhang J, Mazandarani H, Harrison B L, Sabb A, Sabalski J, Stack G,Welmaker G, Barrett J E, Dunlop J (2006) Antiobesity-like effects of the5-HT_(2C) receptor agonist WAY-161503. Brain Res. 1073-1074:240-251.Dunlop J, Sabb A L, Mazandarani H, Zhang J, Kalgaonker S, Shukhina E,Sukoff S, Vogel R L, Stack G, Schechter L, Harrison B L,Rosenzweig-Lipson S (2005). WAY-163909 [97bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole],a novel 5-hydroxytryptamine 2C receptor-selective agonist with anorecticactivity. J Pharmacol Exp Ther. 313:862-869.].

Furthermore, selective 5-HT_(2C) receptor agonists produceantidepressant effects in animal models of depression comparable tothose of SSRIs but with a much faster onset of action and a therapeuticwindow that avoids antidepressant-induced sexual dysfunction. Theseagonists were also effective in animal models of compulsive behaviorsuch as scheduled induced polydipsia and they also exhibited decreasedhyperactivity and aggression in rodents [Rosenzweig-Lipson S, Sabb A,Stack G, Mitchell P, Lucki I, Malberg J E, Grauer S, Brennan J, Cryan JF, Sukoff Rizzo S J, Dunlop J, Barrett J E, Marquis K L (2007)Antidepressant-like effects of the novel, selective, 5-HT_(2C) receptoragonist WAY-163909 in rodents. Psychopharmacology (Berlin) 192:159-170.Rosenzweig-Lipson S, Dunlop J, Marquis K L (2007) 5-HT_(2C) receptoragonists as an innovative approach for psychiatric disorders. Drug newsPerspect, 20: 565-571. Cryan, J F, Lucki I (2000). Antidepressant-likebehavioral effects mediated by 5-Hydroxytryptamine 2C receptors. J.Pharm. Exp. Ther. 295:1120-1126.].

Acute or chronic administration of 5-HT_(2C) agonists decreases thefiring rate of ventral tegmental area dopamine neurons but not that ofsubstantia nigra. In addition 5-HT_(2C) agonists reduce dopamine levelsin the nucleus accumbens but not in the striatum (the region of thebrain mostly associated with extrapyramidal side effects) [Di Matteo,V., Di Giovanni, G., Di Mascio, M., & Esposito, E. (1999). SB 242084, aselective serotonin 2C receptor antagonist, increases dopaminergictransmission in the mesolimbic system. Neuropharmacology 38, 1195-1205.Di Giovanni, G., Di Matteo, V., Di Mascio, M., & Esposito, E. (2000).Preferential modulation of mesolimbic vs. nigrostriatal dopaminergicfunction by serotonin 2C/2B receptor agonists: a combined in vivoelectrophysiological and microdialysis study. Synapse 35, 53-61. MarquisK L, Sabb A L, Logue S F, Brennan J A, Piesla M J, Comery T A, Grauer SM, Ashby C R, Jr., Nguyen H Q, Dawson L A, Barrett J E, Stack G, MeltzerH Y, Harrison B L, Rosenzweig-Lipson S (2007) WAY-163909[(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole]:A novel 5-hydroxytryptamine 2C receptor-selective agonist withpreclinical antipsychotic-like activity. J Pharmacol Exp Ther320:486-496.]. Therefore it is expected that 5-HT_(2C) receptor agonistswill selectively decrease mesolimibic dopamine levels without affectingthe nigrostriatal pathway thus avoiding the EPS side effects of typicalantipsychotics. Several 5-HT_(2C) receptor agonists have shownantipsychotic activity in animal models of schizophrenia without EPSbased on the lack of effect in catalepsy [Marquis K L, Sabb A L, Logue SF, Brennan J A, Piesla M J, Comery T A, Grauer S M, Ashby C R, Jr.,Nguyen H Q, Dawson L A, Barrett J E, Stack G, Meltzer H Y, Harrison B L,Rosenzweig-Lipson S (2007) WAY-163909[(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole]:A novel 5-hydroxytryptamine 2C receptor-selective agonist withpreclinical antipsychotic-like activity. J Pharmacol Exp Ther320:486-496. Siuciak J A, Chapin D S, McCarthy S A, Guanowsky V, BrownJ, Chiang P, Marala R, Patterson T, Seymour P A, Swick A, Iredale P A(2007) CP-809,101, a selective 5-HT_(2C) agonist, shows activity inanimal models of antipsychotic activity. Neuropharmacology 52:279-290].The antipsychotic activity of 5-HT_(2C) receptor agonists without EPScoupled with their beneficial effects in mood disorders and cognitionand their antiobesity like effects render 5-HT_(2C) receptor agonists asunique agents to treat schizophrenia [Rosenzweig-Lipson S, Dunlop J,Marquis K L (2007) 5-HT_(2C) receptor agonists as an innovative approachfor psychiatric disorders. Drug news Perspect, 20: 565-571. Dunlop J,Marquis K L, Lim H K, Leung L, Kao J, Cheesman C, Rosenzweig-Lipson S(2006). Pharmacological profile of the 5-HT_(2C) receptor agonistWAY-163909; therapeutic potential in multiple indications. CNS Dug Rev.12:167-177.].

In addition 5-HT_(2C) modulation has been implicated in epilepsy [IsaacM (2005). Serotonergic 5-HT_(2C) receptors as a potential therapeutictarget for the antiepileptic drugs. Curr. Topics Med. Chem. 5:59:67],psoriasis [Thorslund K, Nordlind K (2007). Serotonergic drugs-a possiblerole in the treatment of psoriasis? Drug News Perspect 20:521-525],Parkinson's disease and related motor disorders [Esposito E, Di MatteoV, Pierucci M, Benigno A, Di Giavanni, G (2007). Role of central5-HT_(2C) receptor in the control of basal ganglia functions. The BasalGanglia Pathophysiology: Recent Advances 97-127], behavioral deficits[Barr A M, Lahmann-Masten V, Paulus M, Gainetdinov R P, Caron M G, GeyerM A (2004). The selective serotonin-2A receptor antagonist M100907reverses behavioral deficits in dopamine transporter knockout mice.Neuropsychopharmacology 29:221-228], anxiety [Dekeyne A, Mannoury laCour C, Gobert A, Brocco M, Lejuene F, Serres F, Sharp T, Daszuta A,Soumier A, Papp M, Rivet J M, Flik G, Cremers T I, Muller O, Lavielle G,Millan M J (2208). S32006, a novel 5-HT_(2C) receptor antagonistsdisplaying broad-based antidepressant and anxiolytic properties inrodent models. Psychopharmacology 199:549-568. Nunes-de-Souza V,Nunes-de-Souza R L, Rodgers R J, Canto-de-Souza A (2008). 5-HT2 receptoractivation in the midbrain periaqueductal grey (PAG) reducesanxiety-like behavior in mice. Behav. Brain Res. 187:72-79.], migraine[Leone M, Rigamonti A, D'Amico D, Grazzi L, Usai S. Bussone G (2001).The serotonergic system in migraine. Journal of Headache and Pain2(Suppl. 1):S43-S46], Alzheimer's disease [Arjona A A, Pooler A M, Lee RK, Wurtman R J (2002). Effect of a 5-HT_(2C) serotonin agonist,dexnorfenfluramine, on amyloid precursor protein metabolism in guineapigs. Brain Res. 951:135-140], pain and spinal cord injury [Nakae A,Nakai K, Tanaka T, Hagihira S, Shibata M, Ueda K, Masimo T (2008). Therole of RNA editing of the serotonin 2C receptor in a rat model oforo-facial neuropathic pain. The European Journal of Neuroscience27:2373-2379. Nakae A, Nakai K, Tanaka T, Takashina M, Hagihira S,Shibata M, Ueda K, Mashimo T (2008). Serotonin 2C receptor mRNA editingin neuropathic pain model. Neurosci. Res. 60:228-231. Kao T, Shumsky JS, Jacob-Vadakot S, Timothy H B, Murray M, Moxon, K A (2006). Role ofthe 5-HT_(2C) receptor in improving weight-supported stepping in adultrats spinalized as neonates. Brain Res. 1112:159-168.], sexualdysfunction [Motofei I G (2008). A dual physiological character forsexual function: the role of serotonergic receptors. BJU International101:531-534. Shimada I, Maeno K, Kondoh Y, Kaku H, Sugasawa K, Kimura Y,Hatanaka K,; Naitou Y, Wanibuchi F, Sakamoto S,; Tsukamoto S (2008).Synthesis and structure-activity relationships of a series ofbenzazepine derivatives as 5-HT_(2C) receptor agonists. Bioorg. Med.Chem. 16:3309-3320.], smoking cessation [Fletcher P J, Le A D, Higgins GA (2008). Serotonin receptors as potential targets for modulation ofnicotine use and dependence. Progress Brain Res. 172:361-83], substancedependence [Bubar M J, Cunningham K A (2008). Prospects for serotonin5-HT2R pharmacotherapy in psychostimulant abuse. Progress Brain Res.172:319-46], and ocular hypertension [Sharif N A, McLaughlin M A, KellyC R (2006). AL-34662: a potent, selective, and efficacious ocularhypotensive serotonin-2 receptor agonist. J Ocul Pharmacol Ther.23:1-13].

Further, 5HT modulation can be useful in the treatment of pain, bothneuropathic and nociceptive pain, see for example U.S. Patentapplication publication US2007/0225277. Obata, Hideaki; Ito, Naomi;Sasaki, Masayuki; Saito, Shigeru; Goto, Fumio. Possible involvement ofspinal noradrenergic mechanisms in the antiallodynic effect ofintrathecally administered 5-HT2C receptor agonists in the rats withperipheral nerve injury. European Journal of Pharmacology (2007),567(1-2), 89-94. Serotonin 2C receptor mRNA editing neuropathic painmodel. Nakae, Aya; Nakai, Kunihiro; Tanaka, Tatsuya; Takashina, Masaki;Hagihira, Satoshi; Shibata, Masahiko; Ueda, Koichi; Mashimo, Takashi.Department of Anesthesiology & Intensive Care Medicine, Graduate Schoolof Medicine, Osaka University, Neuroscience Research (Amsterdam,Netherlands) (2008), 60(2), 228-231. Antiallodynic effects ofintrathecally administered 5-HT2C receptor agonists in rats with nerveinjury. Obata, Hideaki; Saito, Shigeru; Sakurazawa, Shinobu; Sasaki,Masayuki; Usui, Tadashi; Goto, Fumio. Department of Anesthesiology,Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.Pain (2004), 108(1-2), 163-169. Influence of 5,7-dihydroxytryptamine(5,7-DHT) on the antinociceptive effect of serotonin (5-HT) 5-HT2Creceptor agonist in male and female rats. Brus, Ryszard; Kasperska,Alicja; Oswiecimska, Joanna; Szkilnik, Ryszard. Department ofPharmacology, Silesian Medical University, Zabrze, Pol. Medical ScienceMonitor (1997), 3(5), 654-656.

Modulation of 5HT2 receptors may be beneficial in the treatment ofconditions related to bladder function, in particular, urinaryincontinence. [Discovery of a novel azepine series of potent andselective 5-HT2C agonists as potential treatments for urinaryincontinence. Brennan, Paul E.; Whitlock, Gavin A.; Ho, Danny K. H.;Conlon, Kelly; McMurray, Gordon. Bioorganic & Medicinal ChemistryLetters (2009), 19(17), 4999-5003. Investigation of the role of 5-HT2receptor subtypes in the control of the bladder and the urethra in theanesthetized female rat. Mbaki, Y.; Ramage, A. G. Department ofPharmacology, University College London, London, UK. British Journal ofPharmacology (2008), 155(3), 343-356.] In particular, compounds withagonist activity at 5-HT_(2C) have been shown to be useful in treatingurinary incontinence, see for example U.S. Patent applicationpublications US2008/0146583 and US 2007/0225274.

Further pre-clinical data suggest that 5-HT_(2C) agonists could beuseful for the treatment of a number of psychiatric diseases, includingschizophrenia, bipolar disorders, depression/anxiety, substance usedisorders and especially disorders like neuropsychiatric symptoms inAlzheimer's disease: Aggression, psychosis/agitation represent key unmetmedical needs. Clinical (Shen JHQ et al., A 6-week randomized,double-blind, placebo-controlled, comparator referenced trial ofvabicaserin in acute schizophrenia. Journal of Psychiatric Research 53(2014) 14-22; Liu J et al., Prediction of Efficacy of Vabicaserin, a5-HT_(2C) Agonist, for the Treatment of Schizophrenia Using aQuantitative Systems Pharmacology Model. CPT Pharmacometrics Syst.Pharmacol. (2014) 3, e111;) and preclinical data (Dunlop J et al.,Characterization of Vabicaserin (SCA-136), a Selective5-Hydroxytryptamine 2C Receptor Agonist, J Pharmacol Exp Ther (2011)337, 673-80; Siuciak J et al., CP-809,101, a selective 5-HT_(2C)agonist, shows activity in animal models of antipsychotic activity.Neuropharmacology 52 (2007) 279-290; Mosienko V et al., Exaggeratedaggression and decreased anxiety in mice deficient in brain serotonin.Transl Psychiatry (2012) 2, e122; Del Guidice T et al., Stimulation of5-HT_(2C) Receptors Improves Cognitive Deficits Induced by HumanTryptophan Hydroxylase2 Loss of Function Mutation.Neuropsychopharmacology (2014) 39, 1125-1134; Rosenzweig-Lipson et al.,Antidepressant-like effects of the novel, selective, 5-HT_(2C) receptoragonist WAY-163909 in rodents. Psychopharmacology (2007) 192:159-170)suggest 5-HT_(2C) receptor stimulation to result in therapeutic efficacyin aggression, psychosis agitation and moderate pro-cognitive effects(Del Guidice T et al., Stimulation of 5-HT_(2C) Receptors ImprovesCognitive Deficits Induced by Human Tryptophan Hydroxylase2 Loss ofFunction Mutation. Neuropsychopharmacology (2014) 39, 1125-1134; SiuciakJ et al., CP-809,101, a selective 5-HT_(2C) agonist, shows activity inanimal models of antipsychotic activity. Neuropharmacology 52 (2007)279-290).

In the use and the method of the invention, an effective quantity of oneor more compounds, as a rule formulated in accordance withpharmaceutical and veterinary practice, is administered to theindividual to be treated, preferably a mammal, in particular a humanbeing, productive animal or domestic animal. Whether such a treatment isindicated, and in which form it is to take place, depends on theindividual case and is subject to medical assessment (diagnosis) whichtakes into consideration signs, symptoms and/or malfunctions which arepresent, the risks of developing particular signs, symptoms and/ormalfunctions, and other factors.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of the present invention can be varied so as to obtain anamount of the active compound(s) that is effective to achieve thedesired therapeutic response for a particular subject (e.g., a mammal,preferably, a human (patient)), compositions and mode of administration.The selected dosage level will depend upon the activity of theparticular compound, the route of administration, the severity of thecondition being treated and the condition and prior medical history ofthe patient being treated. However, it is within the skill of the art tostart doses of the compound at levels lower than required to achieve thedesired therapeutic effect and to gradually increase the dosage untilthe desired effect is achieved.

Compounds of the present invention can also be administered to a subjectas a pharmaceutical composition comprising the compounds of interest incombination with at least one pharmaceutically acceptable carriers. Thephrase “therapeutically effective amount” of the compound of the presentinvention means a sufficient amount of the compound to treat disorders,at a reasonable benefit/risk ratio applicable to any medical treatment.It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well-known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered toa subject (namely, a mammal, such as a human) ranges from about 0.01mg/kg body weight to about 100 mg/kg body weight. More preferable dosescan be in the range of from about 0.01 mg/kg body weight to about 30mg/kg body weight. If desired, the effective daily dose can be dividedinto multiple doses for purposes of administration. Consequently, singledose compositions may contain such amounts or submultiples thereof tomake up the daily dose.

In one aspect, the present invention provides pharmaceuticalcompositions. The pharmaceutical compositions of the present inventioncomprise the compounds of the present invention or an N-oxide, atautomeric form, a stereoisomer or a pharmaceutically acceptable salt orsolvate thereof. The pharmaceutical compositions of the presentinvention comprise compounds of the present invention that can beformulated together with at least one non-toxic pharmaceuticallyacceptable carrier.

In yet another embodiment, the present invention provides apharmaceutical composition comprising compounds of the present inventionor an N-oxide, a tautomeric form, a stereoisomer or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutically acceptablecarriers, alone or in combination with one or more compounds that arenot the compounds of the present invention. Examples of one or morecompounds that can be combined with the compounds of the presentinvention in pharmaceutical compositions, include, but are not limitedto, one or more cognitive enhancing drugs.

The pharmaceutical compositions of this present invention can beadministered to a subject (e.g., a mammal, such as a human) orally,rectally, parenterally, intracisternally, intravaginally,intraperitoneally, topically (as by powders, ointments or drops),bucally or as an oral or nasal spray. The term “parenterally” as usedherein, refers to modes of administration which include intravenous,intramuscular, intraperitoneal, intrasternal, subcutaneous andintraarticular injection and infusion.

The term “pharmaceutically acceptable carrier” as used herein, means anontoxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions of the present invention for parenteralinjection comprise pharmaceutically acceptable sterile aqueous ornonaqueous solutions, dispersions, suspensions or emulsions as well assterile powders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), vegetable oils (such as olive oil), injectableorganic esters (such as ethyl oleate) and suitable mixtures thereof.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of the presentinvention include powders, sprays, ointments and inhalants. The activecompound may be mixed under sterile conditions with a pharmaceuticallyacceptable carrier and any needed preservatives, buffers or propellantswhich may be required. Ophthalmic formulations, eye ointments, powdersand solutions are also contemplated as being within the scope of thisinvention.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. The phrase “pharmaceutically acceptable salt” means those saltswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al. describe pharmaceutically acceptable saltsin detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq.). Thesalts can be prepared in situ during the final isolation andpurification of the compounds of the invention or separately by reactinga free base function with a suitable organic acid. Representative acidaddition salts include, but are not limited to acetate, adipate,alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate),lactate, malate, maleate, methanesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides such as, but notlimited to, methyl, ethyl, propyl, and butyl chlorides, bromides andiodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamylsulfates; long chain halides such as, but not limited to, decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides; arylalkyl halideslike benzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulfuric acid, and phosphoric acid and such organic acids as aceticacid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinicacid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as, but not limited to,the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine. Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas, but not limited to, lithium, sodium, potassium, calcium, magnesiumand aluminum salts and the like and nontoxic quaternary ammonia andamine cations including ammonium, tetramethylammonium,tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium,triethylammonium, diethylammonium, ethylammonium and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include ethylenediamine, ethanolamine, diethanolamine, piperidine,piperazine and the like.

The compounds of the present invention can exist in unsolvated as wellas solvated forms, including hydrated forms, such as hemi-hydrates. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water and ethanol among others are equivalent to the unsolvatedforms for the purposes of the invention.

The following examples serve to explain the invention without limitingit.

EXAMPLES

The compounds were either characterized via proton-NMR ind₆-dimethylsulfoxide, d-chloroform or d₄-methanol on a 400 MHz, 500 MHzor 600 MHz NMR instrument (Bruker AVANCE), or by ¹³C-NMR at 125 MHz, orby ¹⁹F-NMR at 470 MHz, or by mass spectrometry, generally recorded viaHPLC-MS in a fast gradient on C18-material (electrospray-ionisation(ESI) mode).

The magnetic nuclear resonance spectral properties (NMR) refer to thechemical shifts (δ) expressed in parts per million (ppm). The relativearea of the shifts in the ¹H-NMR spectrum corresponds to the number ofhydrogen atoms for a particular functional type in the molecule. Thenature of the shift, as regards multiplicity, is indicated assinglet(s), broad singlet (s. br.), doublet (d), broad doublet (d br.),triplet (t), broad triplet (t br.), quartet (q), quintet (quint.),multiplet (m), doublet of doublets (dd), doublet of doublets of doublets(ddd), triplet of doublets (td), doublet of triplets of doublets (dtd),quartet of doublets of doublets (qdd) etc.

Enantiomers were separated/purified by chiral supercritical fluidchromatography (SFC) (method A).

Method A

A.1 Analytical SFC

Analytical samples were run on an Agilent 1260 Infinity Hybrid SFCSystem, controlled by Agilent OpenLab CDS ChemStation Edition. Thesystem consists of an injector, a heated column compartment including aswitch for 6 columns, a CO₂-booster pump, a binary pump module for CO₂and modifier flow and an UV-detector. The backpressure regulator was setto 160 bars and heated to 60° C. If not stated otherwise, the columnswere 100 mm in length, 4.6 mm in diameter and packed with 5 μm material.They were kept at room temperature during analysis. As mobile phase, amixture of liquefied CO₂ and organic modifier with additive was used asindicated for each sample. The flow rate was kept at 3.5 mL/min.

A.2 Preparative SFC

Preparative separations were carried out on a Waters Prep 100q SFCSystem, controlled by Waters MassLynx Software. The system consists ofan open bed injector/collector, a heated column compartment including aswitch for 6 columns, a CO₂-booster pump, a pump module for modifierflow and an UV-detector. To enable quantitative collection, the gasliquid separator was driven with a make-up flow of 30 mL/min Methanol.The backpressure regulator was not to 120 bar and heated to 60° C. Ifnot stated otherwise, the columns were 250 mm in length, 20 mm indiameter and packed with 5 μm material. They were kept at 30° C. duringthe separation. As mobile phase, a mixture of liquefied CO₂ and organicmodifier with additive was used as indicated for each sample. The flowrate was kept at 100 g/min.

Abbreviations:

h hour(s)

min minute(s)

d day(s)

r.t. room temperature (20-25° C.)

PE petroleum ether

EtOH ethanol

MeOH methanol

DCM dichloromethane

DCE dichloroethane

THF tetrahydrofuran

DMF N,N-dimethylformamide

MeCN acetonitrile

EtOAc ethyl acetate

TFA trifluoroacetic acid

DIPEA diisopropylethyl amine

EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

HOBt hydroxybenzotriazole

I. Preparation Examples

Example 18-(Trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(Compound of Formula Ia.1 Wherein R^(4a), R^(4b), R^(5a), R^(5b) andR^(7a) are Hydrogen and R⁶ is CF₃) 1.14-(Trifluoromethyl)-3,4-dihydroquinolin-2(1H)-one

In a 5 mL microwave vial containing 100 mg of ethyl(E)-4,4,4-trifluorobut-2-enoate (0.595 mmol, 1.00 eq), 163 mg of2-aminophenyl boronic ester (1.19 mmol, 2.00 eq), 164 mg of potassiumcarbonate (1.19 mmol, 2.00 eq) and 13.6 mg of [RhOH(COD)]₂ (0.030 mmol,0.05 eq) was added 2% wt. TPGS-750-M solution in water (3 mL)(TPGS-750-M: a surfactant composed of a lipophilic α-tocopherol moietyand a hydrophilic PEG-750-M chain, joined by a succinic acid linker;forms spontaneously micelles upon dissolution in water. FromSigma-Aldrich.). The mixture was stirred vigorously at ambienttemperature for 48 h. The reaction mixture was then extracted with ethylacetate. Then the organic phase was dried over MgSO₄, filtrated andreduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-10% methanol in dichloromethane) toyield the title compound (116 mg, 82% yield).

¹H NMR (500 MHz, CDCl₃): δ 9.05 (s, 1H), 7.32 (td, J=7.7, 1.5 Hz, 1H),7.29 (d, J=7.5 Hz, 1H), 7.08 (td, J=7.6, 1.2 Hz, 1H), 6.90 (dd, J=8.0,1.2 Hz, 1H), 3.64 (qdd, J=9.6, 7.1., 2.9 Hz, 1H), 3.00-2.89 (m, 2H).

¹³C NMR (125 MHz, CDCl₃): δ 168.39, 137.83, 130.38, 130.08, 126.12 (q,J=281.0 Hz), 123.43, 116.30, 115.57, 41.15 (q, J=28.6 Hz), 30.07 (q,J=2.8 Hz).

¹⁹F NMR (470 MHz, CDCl₃): δ −72.51.

ESI-MS: m/z (%): 216.20 (100, [M+H]⁺).

1.2 4-(Trifluoromethyl)-1,2,3,4-tetrahydroquinoline

197 mg of 4-(trifluoromethyl)-3,4-dihydroquinolin-2(1H)-one from step1.1 (0.916 mmol, 1.00 eq) was dissolved in 10 mL of THF (anhydrous) and2.29 mL borane dimethyl sulfide complex (2 M in THF, 4.58 mmol, 5.00 eq)was slowly added. The mixture was heated in a microwave at 90° C. for 8h. Then the reaction mixture was quenched with HCl (1 M) and the aqueousphase was extracted with ethyl acetate. Subsequently the organic phasewas extracted three times with HCl (1M) and to the aqueous phase wasadded NaOH (1M) until pH 10. The mixture was then extracted withdichloromethane three times. The organic phase was dried over MgSO₄ andreduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-10% methanol in dichloromethane) toyield the title compound (114 mg, 62% yield).

ESI-MS: m/z (%): 202.20 (100, [M+H]⁺).

1.3 2-(4-(Trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)acetamide

A mixture of 114 mg of 4-(trifluoromethyl)-1,2,3,4-tetrahydroquinolinefrom step 1.2 (0.567 mmol, 1.00 eq), 210 mg of 2-iodoacetamide (1.13mmol, 2.00 eq) and 0.385 ml of DIPEA (2.27 mmol, 4.00 eq) in DMF (3 mL)was heated in a microwave at 130° C. for 8 h. Then NaOH (1M) was addedand the mixture was extracted with dichloromethane. The organic phasewas dried over MgSO₄ and reduced under vacuum. The crude product waspurified by column chromatography on silica (eluent: 0-10% methanol indichloromethane) to yield the title compound (86 mg, 59% yield).

ESI-MS: m/z (%): 259.20 (100, [M+H]⁺).

1.4 2-(4-(Trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine

86 mg of 2-(4-(trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)acetamidefrom step 1.3 (0.333 mmol, 1.00 eq) was dissolved in 3 mL THF(anhydrous) and 0.833 mL of borane dimethyl sulfide complex (2 M THF,1.67 mmol, 5.00 eq) was slowly added. The mixture was heated in amicrowave at 90° C. for 5 h. Then the reaction mixture was quenched withHCl (1 M) and the aqueous phase was extracted with ethyl acetate.Subsequently the organic phase was extracted three times with HCl (1M)and to the aqueous phase was added NaOH (1M) until pH 10. The mixturewas then extracted with dichloromethane three times. The organic phasewas dried over MgSO₄ and reduced under vacuum. The crude product waspurified by column chromatography on silica (eluent: 0-10% methanol indichloromethane) to yield the title compound (69 mg, 85% yield).

ESI-MS: m/z (%): 245.15 (100, [M+H]⁺).

1.58-(Trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

A mixture of 69 mg of2-(4-(trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine from step1.4 (0.282 mmol, 1.00 eq), 0.022 mL of formaldehyde (0.282 mmol, 1.00eq), and 0.022 mL of TFA (0.282 mmol, 1.00 eq) in ethanol (2 mL) wasstirred for 3 d at ambient temperature. Then NaOH (1M) was added and themixture was extracted with dichloromethane. The organic phase was driedover MgSO₄ and reduced under vacuum. The crude product was purified bycolumn chromatography on silica (eluent: 0-10% methanol indichloromethane) to yield the title compound (47 mg, 65% yield).

¹H NMR (500 MHz, CDCl₃) δ 7.17 (d, J=7.4 Hz, 1H), 7.09 (dd, J=7.5, 1.6Hz, 1H), 6.81 (t, J=7.5 Hz, 1H), 3.98 (d, J=14.4 Hz, 1H), 3.85 (d,J=14.5 Hz, 1H), 3.49 (qdd, J=9.8, 6.1, 3.8 Hz, 1H), 3.31 (ddd, J=10.1,3.6, 1.4 Hz, 2H), 3.17-3.01 (m, 4H), 2.20 (dq, J=14.2, 4.0 Hz, 1H),2.10-1.97 (m, 2H).

ESI-MS: m/z (%): 257.20 (100, [M+H]⁺).

1.6 Analytical Separation of the Two Enantiomers of8-(trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolineObtained in Step 1.5

The separation was carried out in two steps via method A.

Two peaks were separated on a Daicel Chiralpak® AS-H column (150×4.6 mm,5 μm) (t_(R) [min]=1.4, 1.7). The gradient used holds at 95% CO₂ and 5%modifier for 1 min. During 7 mins, it raises up to 50% modifier, whichis then held for 1 min. Afterwards, the modifier is ramped back to 5%over 1 min (10 min total). As modifier, MeOH with 0.1 Vol % ofdiethylamine was used.

Enantiomer 1.A of8-(trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolone(Single Enantiomer of Compound 1.5)

ESI-MS: m/z (%): 257.20 (100, [M+H]⁺).

The retention time according to the method described above is 1.4 min.

Enantiomer 1.B of8-(trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolone(Single Enantiomer of Compound 1.5)

ESI-MS: m/z (%): 257.20 (100, [M+H]⁺).

The retention time according to the method described above is 1.7 min.

Example 28-(2,2,2-Trifluoroethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(Compound of Formula Ia.1 Wherein R^(4a), R^(4b), R^(5a), R^(5b) andR^(7a) are hydrogen and R⁶ is CH₂CF₃) 2.14-(2,2,2-Trifluoroethyl)-3,4-dihydroquinolin-2(1H)-one

In a 5 mL microwave vial containing ethyl(E)-5,5,5-trifluoropent-2-enoate (100 mg, 0.549 mmol, 1.00 eq),2-aminophenyl boronic ester (150 mg, 1.10 mmol, 2.00 eq), potassiumcarbonate (152 mg, 1.10 mmol), 2.00 eq) and [RhOH(COD)]₂ (12.52 mg,0.027 mmol, 0.05 eq) was added 2% wt. TPGS-750-M solution in water (3mL). The mixture was stirred vigorously at ambient temperature for 24 h.The reaction mixture was then extracted with ethyl acetate. Then theorganic phase was dried over MgSO₄, filtrated and reduced under vacuum.The crude product was purified by column chromatography on silica(eluent: 0-10% methanol in dichloromethane) to yield the title compound(94 mg, 75% yield).

¹H NMR (500 MHz, CDCl₃): δ 9.28 (s, 1H), 7.28-7.17 (m, 2H), 7.05 (td,J=7.5, 1.2 Hz, 1H), 6.92-6.86 (m, 1H), 3.40 (dq, J=9.1, 5.0 Hz, 1H),2.84 (dd, J=16.4, 5.9 Hz, 1H), 2.71 (dd, J=16.4, 3.6 Hz, 1H), 2.47-2.32(m, 2H).

¹³C NMR (125 MHz, CDCl₃): δ 170.43, 136.39, 128.62, 127.67, 126.20 (q,J=277.0 Hz), 124.94, 123.67, 116.23, 37.82 (q, J=27.6 Hz), 35.80, 30.96.

¹⁹F NMR (470 MHz, CDCl₃): δ −63.33 (t, J=10.6 Hz).

ESI-MS: m/z (%): 230.20 (100, [M+H]⁺).

2.2 4-(2,2,2-Trifluoroethyl)-1,2,3,4-tetrahydroquinoline

229 mg of 4-(2,2,2-trifluoroethyl)-3,4-dihydroquinolin-2(1H)-one fromstep 2.1 (0.999 mmol, 1.00 eq) was dissolved in 10 mL of THF (anhydrous)and 2.50 mL of borane dimethyl sulfide complex (2 M THF, 5.00 mmol, 5.00eq) was slowly added. The mixture was heated in a microwave at 90° C.for 8 h. Then the reaction mixture was quenched with HCl (1 M) and theaqueous phase was extracted with ethyl acetate. Subsequently the organicphase was extracted three times with HCl (1M) and to the aqueous phasewas added NaOH (1M) until pH 10. This was then extracted withdichloromethane three times. The organic phase was dried over MgSO₄ andreduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-10% methanol in dichloromethane) toyield the title compound (170 mg, 79% yield).

ESI-MS: m/z (%): 216.20 (100, [M+H]⁺).

2.2 2-(4-(2,2,2-Trifluoroethyl)-3,4-dihydroquinolin-1(2H)-yl)acetamide

A mixture of 170 mg of4-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinoline from step 2.2(0.790 mmol, 1.00 eq), 292 mg of 2-iodoacetamide (1.58 mmol, 2.00 eq)and 0.537 mL of DIPEA (3.16 mmol, 4.00 eq) in DMF (3 mL) was heated in amicrowave at 110° C. for 8 h and further 3 h at 130° C. Then NaOH (1M)was added and the mixture was extracted with dichloromethane. Theorganic phase was dried over MgSO₄ and reduced under vacuum. The crudeproduct was purified by column chromatography on silica (eluent: 0-10%methanol in dichloromethane) to yield the title compound (168 mg, 78%yield).

ESI-MS: m/z (%): 273.20 (100, [M+H]⁺).

2.3 2-(4-(2,2,2-Trifluoroethyl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine

165 mg of2-(4-(2,2,2-trifluoroethyl)-3,4-dihydroquinolin-1(2H)-yl)acetamide fromstep 2.2 (0.606 mmol, 1.00 eq) was dissolved in 4 mL of THF (anhydrous)and 0.61 mL of borane dimethyl sulfide complex (2 M THF, 1.212 mmol,2.00 eq) was slowly added. The mixture was heated in a microwave at 90°C. for 2 h. Then the reaction mixture was quenched with HCl (1 M) andthe aqueous phase was extracted with ethyl acetate. Subsequently theorganic phase was extracted three times with HCl (1M) and to the aqueousphase was added NaOH (1M) until pH 10. This was then extracted withdichloromethane three times. The organic phase was dried over MgSO₄ andreduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-10% methanol in dichloromethane) toyield the title compound (90 mg, 52% yield).

ESI-MS: m/z (%): 259.20 (100, [M+H]⁺).

2.48-(2,2,2-Trifluoroethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

A mixture of 90 mg of2-(4-(2,2,2-trifluoroethyl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine fromstep 2.3 (0.314 mmol, 1.00 eq), 23 μL of formaldehyde (0.314 mmol, 1.00eq) and 27 μL of TFA (0.314 mmol, 1.00 eq) was stirred at ambienttemperature for 72 h. Then NaOH (1M) was added and the mixture wasextracted with dichloromethane. The organic phase was dried over MgSO₄and reduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-10% methanol in dichloromethane) toyield the title compound (62 mg, 72% yield).

¹H NMR (600 MHz, DMSO-d₆) δ 7.01 (dd, J=7.7, 1.5 Hz, 1H), 6.95 (dd,J=7.3, 1.6 Hz, 1H), 6.72 (t, J=7.4 Hz, 1H), 3.72 (d, J=14.1 Hz, 1H),3.64 (d, J=14.1 Hz, 1H), 3.21-3.17 (m, 2H), 3.13-3.07 (m, 1H), 3.03-2.96(m, 2H), 2.93-2.83 (m, 2H), 1.81-1.73 (m, 1H), 3.47-3.43 (m, 1H),2.67-2.51 (m, 2H), 1.92-1.83 (m, 1H).

ESI-MS: m/z (%): 271.20 (100, [M+H]⁺).

Example 38-(Difluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(Compound of Formula Ia.1 Wherein R^(4a), R^(4b), R^(5a), R^(5b) andR^(7a) are hydrogen and R⁶ is CHF₂) 3.14-(Difluoromethyl)-3,4-dihydroquinolin-2(1H)-one

In a 5 mL microwave vial containing ethyl (E)-4,4-difluorobut-2-enoate(110 mg, 0.67 mmol, 1.00 eq), 2-aminophenyl boronic ester (183 mg, 1.33mmol, 2.00 eq), potassium carbonate (184 mg, 1.33 mmol), 2.00 eq) and[RhOH(COD)]₂ (15 mg, 0.033 mmol, 0.05 eq) was added 2% wt. TPGS-750-Msolution in water (3 mL). The mixture was stirred vigorously at ambienttemperature for the 24 h. The reaction mixture was then extracted withethyl acetate. Then the organic phase was dried over MgSO₄, filtratedand reduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-10% methanol in dichloromethane) toyield the title compound (70 mg, 50% yield).

¹H NMR (500 MHz, CDCl₃): δ 9.05 (s, 1H), 7.27 (dtd, J=15.4, 7.7, 1.4 Hz,2H), 7.06 (td, J=7.5, 1.1 Hz, 1H), 6.88 (dd, J=7.9, 1.2 Hz, 1H), 5.85(td, J=56.0, 4.3 Hz, 1H), 5.74 (d, J=4.3 Hz, 1H), 3.44-3.33 (m, 1H),2.94-2.82 (m, 2H).

¹³C NMR (125 MHz, CDCl₃): δ 169.41, 137.65, 129.55, 129.46, 123.48,117.92 (t, J=3.8 Hz), 116.26 (t, J=245.4 Hz), 116.12, 40.95 (t, J=22.1Hz), 29.64.

¹⁹F NMR (470 MHz, CDCl₃): δ −120.87 (ddd, J=280.0, 55.9, 13.4 Hz),−123.60 (ddd, J=280.1, 56.2, 16.5 Hz).

ESI-MS: m/z (%): 198.10 (100, [M+H]⁺).

3.2 4-(Difluoromethyl)-1,2,3,4-tetrahydroquinoline

390 mg of 4-(difluoromethyl)-3,4-dihydroquinolin-2(1H)-one from step 3.1(1.98 mmol, 1.00 eq) was dissolved in 4 mL of THF (anhydrous) and 3.96mL of borane dimethyl sulfide complex (2 M in THF, 7.92 mmol, 4.00 eq)was slowly added. The mixture was heated in a microwave at 90° C. for 10h. Then the reaction mixture was quenched with HCl (1 M) and the aqueousphase was extracted with ethyl acetate. Subsequently the organic phasewas extracted three times with HCl (1M) and to the aqueous phase wasadded NaOH (1M) until pH 10. This was then extracted withdichloromethane three times. The organic phase was dried over MgSO₄ andreduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-10% methanol in dichloromethane) toyield the title compound (220 mg, 55% yield).

ESI-MS: m/z (%): 184.10 (100, [M+H]⁺).

3.3 2-(4-(Difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)acetamide

A mixture of 220 mg of 4-(difluoromethyl)-1,2,3,4-tetrahydroquinolinefrom step 3.2 (1.20 mmol, 1.00 eq), 666 mg of 2-iodoacetamide (3.60mmol, 3.00 eq) and 1 mL of DIPEA (6.00 mmol, 500 eq) in DMF (3 mL) washeated in a microwave at 100° C. for 11 h. Then NaOH (1M) was added andthe mixture was extracted with dichloromethane. The organic phase wasdried over MgSO₄ and reduced under vacuum. The crude product waspurified by column chromatography on silica (eluent: 0-10% methanol indichloromethane) to yield the title compound (260 mg, 90% yield).

ESI-MS: m/z (%): 241.20 (100, [M+H]⁺).

3.4 2-(4-(Difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine

260 mg of 2-(4-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)acetamidefrom step 3.3 (1.08 mmol, 1.00 eq) was dissolved in 3 mL of THF(anhydrous) and 2.71 mL of borane dimethyl sulfide complex (2 M in THF,5.41 mmol, 5.00 eq) was slowly added. The mixture was heated in amicrowave at 90° C. for 5 h. Then the reaction mixture was quenched withHCl (1 M) and the aqueous phase was extracted with ethyl acetate.Subsequently the organic phase was extracted three times with HCl (1M)and to the aqueous phase was added NaOH (1M) until pH 10. This was thenextracted with dichloromethane three times. The organic phase was driedover MgSO₄ and reduced under vacuum. The crude product was purified bycolumn chromatography on silica (eluent: 0-10% methanol indichloromethane) to yield the title compound (155 mg, 57% yield).

ESI-MS: m/z (%): 227.20 (100, [M+H]⁺).

3.58-(Difluoromethyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

A mixture of 155 mg of2-(4-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine from step3.4 (0.685 mmol, 1.00 eq), 0.055 mL of formaldehyde (0.719 mmol, 1.05eq), and 0.058 mL of TFA (0.754 mmol, 1.10 eq) in ethanol (2 mL) wasstirred for 7 h at ambient temperature. Then NaOH (1M) was added and themixture was extracted with dichloromethane. The organic phase was driedover MgSO₄ and reduced under vacuum. The crude product was purified bycolumn chromatography on silica (eluent: 0-20% methanol indichloromethane+0.1% NH₃ in ethanol) to yield the title compound (51 mg,26% yield).

¹H NMR (600 MHz, DMSO-d₆) δ 8.83 (s, 1H), 7.34-7.21 (m, 2H), 6.91 (t,J=7.5 Hz, 1H), 6.35 (td, J=56.1, 4.2 Hz, 1H), 4.18 (dt, J=24.4, 4.4 Hz,2H), 3.31-3.20 (m, 7H), 2.02-1.83 (m, 2H).

ESI-MS: (%): 239.20 (100, [M+H]⁺).

Example 44-Methyl-8-(trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(Compound of Formula Ia.10 Wherein R^(4a), R^(4b), R^(5a), R^(5b) andR^(7a) are hydrogen and R⁶ is CF₃) 4.1 Ethyl2-(4-(trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)propanoate

A mixture of 1.57 g of 4-(trifluoromethyl-1,2,3,4-tetrahydroquinoline(7.80 mmol, 1.00 eq) from step 1.2, 14.1 g of ethyl 2-bromopropanoate(78.0 mmol, 10.0 eq and 15.1 mL of DIPEA (117 mmol, 15.0 eq) in DMF (38mL) was heated in a microwave for 1 h at 175° C. Then the mixture wasdiluted with ethyl acetate and washed with aqueous sodium bicarbonatesolution. The aqueous phase was extracted three times with ethyl acetateand the combined organic phases were dried over Na₂SO₄, filtrated andconcentrated in vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-30% methanol in dichloromethane) toyield the title compound.

ESI-MS: m/z (%): 302.20 (100, [M+H]⁺).

4.2 2-(4-(Trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)propanoic acid

A mixture of 2.59 g of ethyl2-(4-(trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)propanoate (8.60mmol, 1.00 eq) from step 4.1 and 43.0 mL of NaOH (1M in H₂O, 43.0 mmol,5.00 eq) in MeOH (40 mL) was stirred at room temperature for 16 h. Thensaturated aqueous sodium bicarbonate solution was added and the mixturewas washed with ethyl acetate. 1M HCl was added to the aqueous phaseuntil pH 3 was reached. The aqueous phase was extracted 5 times with DCMand the organic phase was dried over Na₂SO₄, filtrated and concentratedin vacuum to yield the title compound (47%, 4.02 mmol).

ESI-MS: m/z (%): 274.20 (100, [M+H]⁺).

4.3 2-(4-(Trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)propanamide

To a solution of 1.10 g of2-(4-(trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)propanoic acid (4.02mmol, 1.00 eq) from step 4.2, 430 mg of ammonium chloride (8.04 mmol,2.00 eq) and 0.702 mL of DIPEA (4.02 mmol, 1.00 eq) in DMF (20 mL) wasadded 1.54 g of EDC (8.04 mmol, 2.00 eq) and 616 mg HOBt (4.02 mmol,1.00 eq) and the mixture was stirred for 16 h at room temperature. ThenDCM was added and the mixture was washed with saturated aqueous sodiumbicarbonate solution. The organic layer was dried over Na₂SO₄, filtratedand reduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-30% methanol in dichloromethane) toyield the title compound (86%, 3.46 mmol).

ESI-MS: m/z (%): 273.20 (100, [M+H]⁺).

4.4 2-(4-(Trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)propan-1-amine

To 942 mg of2-(4-(trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)propanamide (3.46mmol, 1.00 eq) from step 4.3 and 8.65 mL of borane dimethyl sulfidecomplex (1 M in THF, 17.3 mmol, 5.00 eq) was slowly added. The mixturewas stirred for 72 h at room temperature and was then heated at 90° C.for 2 h. Then the reaction mixture was quenched with HCl (1 M) and theaqueous phase was extracted with ethyl acetate. The organic phase wasextracted three times with HCl (1M) and to the aqueous phase was addedNaOH (1M) until pH 10 and was then extracted with dichloromethane threetimes. The organic phase was dried over MgSO₄ and reduced under vacuum.The crude product was purified by column chromatography on silica(eluent: 0-30% methanol in dichloromethane) to yield the title compound(1.68 mmol, 49%).

ESI-MS: m/z (%): 259.20 (100, [M+H]⁺).

4.54-Methyl-8-(trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

A mixture of 444 mg of2-(4-(trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)propan-1-amine (1.72mmol, 1.00 eq) from step 4.4, 0.128 mL of formaldehyde (1.72 mmol, 1.00eq) and 0.146 mL of TFA (1.89 mmol, 1.10 eq) was stirred at ambienttemperature for 72 h. Then the solvent was removed under vacuum. Theresidue was dissolved with DCM and washed with saturated aqueous sodiumbicarbonate solution. The organic layer was dried over Na₂SO₄, filtratedand reduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-30% methanol in dichloromethane) toyield the title compound (40%, 0.688 mmol).

ESI-MS: m/z (%): 271.20 (100, [M+H]⁺).

4.6 Analytical Separation of the Four Isomers of4-methyl-8-(trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolineObtained in Step 4.5

Four peaks were separated on a Daicel Chiralcel® OD-H column (t_(R)[min]=1.5, 1.7, 1.9, 2.2). The mobile phase consisted of 93% CO₂ and 7%modifier. As modifier, MeOH with 0.2 Vol % of aqueous ammonia solution(25%) was used.

4.7 Preparative Separation of the Four Isomers of4-methyl-8-(trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolineObtained in Step 4.5

All 4 Isomers were separated in one step by UV-detection at 254 nm:

Four peaks were separated on a Daicel Chiralcel® OD-H column (250×20 mm,5 μm) (t_(R) [min]=4.6, 5.1, 6.1, 6.6). The mobile phase consisted of95% CO₂ and 5% modifier. As modifier, MeOH with 0.2 Vol % of aqueousammonia solution (25%) was used.

Isomer 4.A of4-methyl-8-(trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(Single Enantiomer of Diastereomer 1 of the Compound of Step 4.5)

ESI-MS: m/z (%): 271.20 (100, [M+H]⁺).

The retention time according to the analytical method described above is1.5 min and according to the preparative method described above is 4.6min.

¹H NMR (600 MHz, CDCl₃): δ 7.20 (d, J=8.0, 1.8 Hz, 1H), 7.10-7.06 (m,1H), 6.82 (t, J=7.5 Hz, 1H), 3.98 (d, J=13.6 Hz, 1H), 3.74 (d, J=13.7Hz, 1H), 3.53-3.42 (m, 1H), 3.42-3.34 (m, 1H), 3.34-3.24 (m, 2H), 3.12(dd, J=13.5, 2.6 Hz, 1H), 2.81 (dd, J=13.5, 3.8 Hz, 1H), 2.19-2.02 (m,2H), 1.07 (d, J=6.8 Hz, 3H). (NH not detected)

Isomer 4.B of4-methyl-8-(trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(Single Enantiomer of Diastereomer 1 of the Compound of Step 4.5)

ESI-MS: m/z (%): 271.20 (100, [M+H]⁺).

The retention time according to the analytical method described above is1.7 min and according to the preparative method described above is 5.1min.

¹H NMR (600 MHz, CDCl₃): δ 7.21 (d, J=7.8 Hz, 1H), 7.11-7.07 (m, 1H),6.82 (t, J=7.5 Hz, 1H), 4.00 (d, J=13.6 Hz, 1H), 3.76 (d, J=13.6 Hz,1H), 3.53-3.45 (m, 1H), 3.40-3.34 (m, 1H), 3.34-3.25 (m, 2H), 3.13 (dd,J=13.6, 2.6 Hz, 1H), 2.83 (dd, J=13.5, 3.8 Hz, 1H), 2.18-2.02 (m, 2H),1.10 (d, J=6.8 Hz, 3H). (NH not detected)

Isomer 4.C of4-methyl-8-(trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(Single Enantiomer of Diastereomer 2 of the Compound of Step 4.5)

ESI-MS: m/z (%): 271.20 (100, [M+H]⁺).

The retention time according to the analytical method described above is1.9 min and according to the preparative method described above is 6.1min.

¹H NMR (600 MHz, CDCl₃): δ 7.19 (d, J=7.7 Hz, 1H), 7.13 (dd, J=7.5, 1.6Hz, 1H), 6.82 (t, J=7.5 Hz, 1H), 4.11 (d, J=14.0 Hz, 1H), 3.70 (d,J=14.0 Hz, 1H), 3.45 (dt, J=9.8, 5.3 Hz, 1H), 3.36 (td, J=6.7, 3.4 Hz,2H), 3.31 (ddd, J=12.5, 3.7, 1.4 Hz, 1H), 3.08 (dd, J=13.6, 2.7 Hz, 1H),3.02 (dd, J=13.5, 3.2 Hz, 1H), 2.33-2.14 (m, 1H), 2.06-1.92 (m, 1H),1.00 (d, J=6.8 Hz, 3H). (NH not detected)

Isomer 4.D of4-methyl-8-(trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(Single Enantiomer of Diastereomer 2 of the Compound of Step 4.5)

ESI-MS: m/z (%): 271.20 (100, [M+H]⁺).

The retention time according to the analytical method described above is2.2 min and according to the preparative method described above is 6.6min.

¹H NMR (600 MHz, CDCl₃): δ 7.15 (d, J=7.8 Hz, 1H), 7.09 (dd, J=7.4, 1.6Hz, 1H), 6.79 (t, J=7.5 Hz, 1H), 4.03 (d, J=14.1 Hz, 1H), 3.62 (d,J=14.2 Hz, 1H), 3.49-3.40 (m, 1H), 3.39-3.25 (m, 3H), 3.05 (dd, J=13.7,2.7 Hz, 1H), 2.93 (dd, J=13.6, 3.1, 0.9 Hz, 1H), 2.26 (dq, J=14.3, 3.6Hz, 1H), 2.06-1.92 (m, 1H), 0.92 (d, J=6.9 Hz, 3H). (NH not detected)

Example 58-(Difluoromethyl)-4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(Compound of Formula Ia.10 Wherein R^(4a), R^(4b) , R^(5a), R^(5b) andR^(7a) are hydrogen and R⁶ is CHF₂) 5.1 Ethyl2-(4-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)propanoate

A mixture of 416 mg of 4-(difluoromethyl)-1,2,3,4-tetrahydroquinoline(2.27 mmol, 1.00 eq) from step 3.2, 4.11 g of ethyl 2-bromopropanoate(22.7 mmol, 10.0 eq and 5.95 mL DIPEA (34.1 mmol, 15.0 eq) in DMF (10mL) was heated in a microwave for 1 h at 150° C. Then the mixture wasdiluted with ethyl acetate and washed with aqueous sodium bicarbonatesolution. The aqueous phase was extracted three times with ethyl acetateand the combined organic phases were dried over Na₂SO₄, filtrated andconcentrated in vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-30% methanol in dichloromethane) toyield the title compound.

ESI-MS: m/z (%): 284.20 (100, [M+H]⁺).

5.2 2-(4-(Difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)propanoic acid

A mixture of 1.07 g of ethyl2-(4-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)propanoate (3.78mmol, 1.00 eq) from step 5.1 and 18.9 mL of NaOH (1M in H₂O, 18.9 mmol,5.00 eq) MeOH (20 mL) was stirred at room temperature for 16 h. Thensaturated aqueous sodium bicarbonate solution was added and the mixturewas washed with ethyl acetate. 1M HCl was added to the aqueous phaseuntil pH 3 was reached. The aqueous phase was extracted 5 times with DCMand the organic phase was dried over Na₂SO₄, filtrated and concentratedin vacuum to yield the title compound (55%, 2.06 mmol).

ESI-MS: m/z (%): 256.30 (100, [M+H]⁺).

5.3 2-(4-(Difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)propanamide

To a solution of 526 mg of2-(4-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)propanoic acid (2.06mmol, 1.00 eq) from step 5.2, 220 mg of ammonium chloride (4.12 mmol,2.00 eq) and 0.360 mL of DIPEA (2.06 mmol, 1.00 eq) in DMF (10 mL) wasadded 789 mg of EDC (4.12 mmol, 2.00 eq) and 315 mg of HOBt (2.06 mmol,1.00 eq) and the mixture was stirred for 16 h at room temperature. ThenDCM was added and the mixture was washed with saturated aqueous sodiumbicarbonate solution. The organic layer was dried over Na₂SO₄, filtratedand reduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-30% methanol in dichloromethane) toyield the title compound (64%, 1.31 mmol).

ESI-MS: m/z (%): 255.20 (100, [M+H]⁺).

5.4 2-(4-(Difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)propan-1-amine

To 333 mg of2-(4-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)propanamide (1.31mmol, 1.00 eq) from step 5.3 and 6.54 mL of borane dimethyl sulfidecomplex (1 M in THF, 6.54 mmol, 5.00 eq) was slowly added. The mixturewas stirred for 72 h at room temperature and was then heated in amicrowave at 90° C. for 30 min. The reaction mixture was quenched withHCl (1 M) and the aqueous phase was extracted with ethyl acetate. Theorganic phase was extracted three times with HCl (1M) and to the aqueousphase was added NaOH (1M) until pH 10 and was then extracted withdichloromethane three times. The organic phase was dried over MgSO₄ andreduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-30% methanol in dichloromethane) toyield the title compound (0.720 mmol, 55%).

ESI-MS: m/z (%): 241.25 (100, [M+H]⁺).

5.58-(Difluoromethyl)-4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

A mixture of 173 mg of2-(4-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)propan-1-amine (0.720mmol, 1.00 eq) from step 5.4, formaldehyde (0.720 mmol, 1.00 eq) and TFA(0.792 mmol, 1.10 eq) was stirred at ambient temperature for 72 h. Thenthe solvent was removed under vacuum. The residue was dissolved with DCMand washed with saturated aqueous sodium bicarbonate solution. Theorganic layer was dried over Na₂SO₄, filtrated and reduced under vacuum.The crude product was purified by column chromatography on silica(eluent: 0-30% methanol in dichloromethane) to yield the title compound(45%, 0.326 mmol).

ESI-MS: m/z (%): 253.25 (100, [M+H]⁺).

¹H NMR (600 MHz, DMSO-d₆): δ 7.11 (d, J=7.6 Hz, 1H), 6.99 (dd, J=1.5 Hz,1H), 6.74 (t, J=7.5 Hz, 1H), 6.29 (td, J=56.2, 4.1 Hz, 1H), 3.80 (d,J=13.4 Hz, 1H), 3.47 (d, J=13.4 Hz, 1H), 3.40-3.31 (m, 1H), 3.30-3.21(m, 2H), 3.21-3.16 (m, 1H), 2.85 (dd, J=13.2, 2.6 Hz, 1H), 2.68 (dd,J=13.1, 3.5 Hz, 1H), 1.98-1.89 (m, 1H), 1.89-1.80 (m, 1H), 0.91 (d,J=6.7 Hz, 3H). (NH not detected)

5.6 Analytical Separation of the Four Isomers of8-(difluoromethyl)-4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolineObtained in Step 5.5

Three peaks were separated on a Daicel Chiralcel® OD-H column (t_(R)[min]=1.9, 2.1, 2.5). The mobile phase consisted of 93% CO₂ and 7%modifier. As modifier, MeOH with 0.2 Vol % of aqueous ammonia solution(25%) was used.

The second peak could be further separated on a Daicel Chiralpak® AD-Hcolumn (t_(R) [min]=1.8, 2.1). The mobile phase consisted of 93% CO₂ and7% modifier. As modifier, MeOH with 0.2 Vol % of aqueous ammoniasolution (25%) was used.

5.7 Preparative Separation of the Four Isomers of8-(difluoromethyl)-4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolineObtained in Step 5.5

The separation of the 4 isomers was carried out in two steps byUV-detection at 254 nm:

Three peaks were separated on a Daicel Chiralcel® OD-H column (250×20mm, 5 μm) (t_(R) [min]=2.7, 3.2, 3.5). The mobile phase consisted of 90%CO₂ and 10% modifier. As modifier, MeOH with 0.1 Vol % of triethylaminewas used.

The second peak consisted of two isomers, that were subsequentlyseparated on a YMC CHIRAL Amylose-C column (250×20 mm, 5 μm) (t_(R)[min]=3.9, 4.3). The mobile phase consisted of 93% CO2 and 7% modifier.As modifier, MeOH with 0.2 Vol % of aqueous ammonia solution (25%) wasused.

Isomer 5.A of8-(difluoromethyl)-4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(Single Enantiomer of Diastereomer 1 of the Compound of Step 5.5)

ESI-MS: m/z (%): 253.25 (100, [M+H]⁺).

The retention time according to the analytical method described above is1.9 min and according to the preparative method described above is 2.7min.

¹H NMR (600 MHz, DMSO-d₆): δ 7.11 (d, J=7.6 Hz, 1H), 6.99 (dd, J=7.3,1.5 Hz, 1H), 6.74 (t, J=7.5 Hz, 1H), 6.29 (td, J=56.2, 4.1 Hz, 1H), 3.80(d, J=13.4 Hz, 1H), 3.47 (d, J=13.4 Hz, 1H), 3.40-3.31 (m, 1H),3.30-3.21 (m, 2H), 3.21-3.16 (m, 1H), 2.85 (dd, J=13.2, 2.6 Hz, 1H),2.68 (dd, J=13.1, 3.5 Hz, 1H), 1.98-1.89 (m, 1H), 1.89-1.80 (m, 1H),0.91 (d, J=6.7 Hz, 3H). (NH not detected)

Isomer 5.B of8-(difluoromethyl)-4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(Single Enantiomer of Diastereomer 1 of the Compound of Step 5.5)

ESI-MS: m/z (%): 253.25 (100, [M+H]⁺).

The retention time according to the analytical method described above is1.8 min and according to the preparative method described above is 3.9min.

¹H NMR (600 MHz, DMSO-d₆) δ 7.04 (dd, J=7.7, 1.6 Hz, 1H), 6.98 (dd,J=7.3, 1.6 Hz, 1H), 6.70 (t, J=7.4 Hz, 1H), 6.27 (td, J=56.3, 4.8 Hz,1H), 3.84 (d, J=13.5 Hz, 1H), 3.39 (d, J=13.6 Hz, 1H), 3.28-3.12 (m,4H), 2.80 (dd, J=13.1, 2.5 Hz, 1H), 2.73 (dd, J=13.1, 3.1 Hz, 1H),2.07-1.96 (m, 1H), 1.88-1.75 (m, 1H), 0.87 (d, J=6.7 Hz, 3H). (NH notdetected)

Isomer 5.C of8-(difluoromethyl)-4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(Single Enantiomer of Diastereomer 2 of the Compound of Step 5.5)

ESI-MS: m/z (%): 253.25 (100, [M+H]⁺).

The retention time according to the analytical method described above is2.1 min and according to the preparative method described above is 4.3min.

¹H NMR (600 MHz, DMSO-d₆) δ 7.12 (d, J=7.6 Hz, 1H), 7.00 (dd, J=7.3, 1.6Hz, 1H), 6.75 (t, J=7.5 Hz, 1H), 6.29 (td, J=56.2, 4.1 Hz, 1H), 3.81 (d,J=13.4 Hz, 1H), 3.50 (d, J=13.4 Hz, 1H), 3.41-3.28 (m, 1H), 3.30-3.22(m, 2H), 3.22-3.14 (m, 1H), 2.86 (dd, J=13.1, 2.6 Hz, 1H), 2.70 (dd,J=13.1, 3.5 Hz, 1H), 1.98-1.89 (m, 1H), 1.89-1.81 (m, 1H), 0.92 (d,J=6.7 Hz, 3H). (NH not detected)

Isomer 5.D of8-(difluoromethyl)-4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(Single Enantiomer of Diastereomer 2 of the Compound of Step 5.5)

ESI-MS: m/z (%): 253.25 (100, [M+H]⁺).

The retention time according to the analytical method described above is2.5 min and according to the preparative method described above is 3.5min.

¹H NMR (600 MHz, DMSO-d₆) δ 7.05 (dd, J=7.5, 1.6 Hz, 1H), 6.99 (dd,J=7.3, 1.6 Hz, 1H), 6.71 (t, J=7.4 Hz, 1H), 6.27 (td, J=56.4, 4.8 Hz,1H), 3.85 (d, J=13.6 Hz, 1H), 3.41 (d, J=13.6 Hz, 1H), 3.28-3.09 (m,4H), 2.81 (dd, J=13.1, 2.5 Hz, 1H), 2.75 (dd, J=13.1, 3.2 Hz, 1H),2.07-1.96 (m, 1H), 1.86-1.75 (m, 1H), 0.88 (d, J=6.7 Hz, 3H). (NH notdetected)

Example 6(4-Methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-8-yl)methanol(Compound of Formula Ia.10 Wherein R^(4a), R^(4b), R^(5a), R^(5b) andR^(7a) are hydrogen and R⁶ is CH₂OH) 6.1(1-(1-Aminopropan-2-yl)-1,2,3,4-tetrahydroquinolin-4-yl)methanol

500 mg of1-(2-amino-1-methyl-2-oxo-ethyl)-3,4-dihydro-2H-quinoline-4-carboxylicacid (2.014 mmol, 1.00 eq) was dissolved in 1 mL of THF (anhydrous) and5.03 mL of borane dimethyl sulfide complex (2 M in THF, 10.07 mmol, 5.00eq) was slowly added. The mixture was heated in a microwave at 90° C.for 2 h. Then the reaction mixture was quenched with HCl (1 M) and theaqueous phase was extracted with ethyl acetate. The organic phase wasextracted three times with HCl (1M) and to the aqueous phase was addedNaOH (1M) until pH 10 and was then extracted with dichloromethane threetimes. The organic phase was dried over MgSO₄ and reduced under vacuum.The crude product was purified by column chromatography on silica(eluent: 0-10% methanol in dichloromethane) to yield the title compound.

ESI-MS: m/z (%): 221.20 (100, [M+H]⁺).

6.2(4-Methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-8-yl)methanol

A mixture of 61 mg of(1-(1-aminopropan-2-yl)-1,2,3,4-tetrahydroquinolin-4-yl)methanol (0.277mmol, 1.00 eq) obtained in step 6.1, formaldehyde (0.277 mmol, 1.00 eq)and TFA (0.305 mmol, 1.10 eq) was stirred at ambient temperature for 72h. Then the solvent was removed under vacuum. The crude product waspurified by column chromatography on silica (eluent: 0-10% methanol indichloromethane) to yield the title compound as TFA-salt (62%, 0.171mmol).

ESI-MS: m/z (%): 233.30 (100, [M+H]⁺).

Example 78-(Fluoromethyl)-4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(Compound of Formula Ia.10 Wherein R^(4a), R^(4b), R^(5a), R^(5b) andR^(7a) are hydrogen and R⁶ is CH₂F) 7.1 tert-Butyl8-(hydroxymethyl-4-methyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate

487 mg of(4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-8-yl)methanol(2.096 mmol, 1.00 eq) from step 6.2 was dissolved in DCM (15 mL) and0.585 mL of triethylamine (4.19 mmol, 2.00 eq) was added. Then 457 mg(2.096 mmol, 1.00 eq) of di-tert-butyldicarbonat was added and themixture was stirred for 18 h at room temperature. Citric acid was addedand the solution was stirred for 15 min. The organic phase was separatedfrom the aqueous phase and the aqueous phase was extracted with DCM. Theorganic phase was dried over MgSO₄ and reduced under vacuum to yield thetitle compound.

ESI-MS: m/z (%): 333.30 (100, [M+H]⁺).

7.2 tert-Butyl4-methyl-8-(((methylsulfonyl)oxy)methyl)-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate

269 mg of tert-butyl8-(hydroxymethyl)-4-methyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate(0.810 mmol, 1.00 eq) from step 7.1 dissolved in DCM (5 mL) was cooledto 0° C. and 0.226 mL of triethylamine (1.62 mmol, 2.00 eq) was added.Then 0.066 mL of methanesulfonyl chloride (0.850 mmol, 1.05 eq) wasadded and the mixture was stirred for 1 h at 0° C. Then it was warmed upto room temperature and stirred for further 16 h. After quenching withwater the organic phase was separated from the aqueous phase and theaqueous phase was extracted with DCM. The organic phase was dried overMgSO₄ and reduced under vacuum. The crude product was purified by columnchromatography on silica (eluent: 0-100% methanol in DCM) to yield thetitle compound (43%, 0.064 mmol).

ESI-MS: m/z (%): 411.20 (100, [M+H]⁺).

7.3 tert-Butyl8-(fluoromethyl)-4-methyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate

To 54 mg of tert-butyl4-methyl-8-(((methylsulfonyl)oxy)methyl)-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate(0.132 mmol, 1.00 eq) from step 7.2 dissolved in tert-butanol (2 mL) wasadded 80 mg of caesium fluoride (0.526, 4.00 eq). The mixture was heatedfor 2 h in a microwave at 80° C. Then saturated aqueous sodiumbicarbonate solution was added. The organic phase was separated from theaqueous phase and the aqueous phase was extracted with DCM. The organicphase was dried over MgSO₄ and reduced under vacuum to yield the titlecompound.

ESI-MS: m/z (%): 335.30 (100, [M+H]⁺).

7.48-(Fluoromethyl)-4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

To a solution of 78 mg of tert-butyl8-(fluoromethyl)-4-methyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate(0.233 mmol, 1.00 eq) from step 7.3 in DCM (3 mL) was added 0.180 mL oftrifluoroacetic acid (2.33 mmol, 10.00 eq) and the mixture was stirredfor 3 d. Then the solvent was evaporated and the crude product waspurified via column chromatography on silica (eluent: 0-100% ethylacetate in heptane) which yielded the title compound (4.5%,0.010 mmol).

ESI-MS: m/z (%): 235.20 (100, [M+H]⁺).

¹H NMR (500 MHz, Methanol-d₄): δ 7.27-7.25 (m, 1H), 7.19 (dd, J=7.4, 1.5Hz, 1H), 6.94 (td, J=7.6, 2.5 Hz, 1H), 4.84-4.44 (m, 3H), 4.28 (dd,J=13.2, 9.3 Hz, 1H), 4.08 (dd, J=15.8, 13.1 Hz, 1H), 3.70-3.44 (m, 1H),3.43-3.31 (m, 1H), 3.31-3.15 (m, 3H), 2.07-1.85 (m, 1H), 1.96-1.92 (m,1H), 1.31-1.20 (m, 4H).

Example 88-(Ethoxymethyl)-4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(Compound of Formula Ia.10 Wherein R^(4a), R^(4b), R^(5a), R^(5b) andR^(7a) are hydrogen and R⁶ is ethoxymethyl (CH₂OCH₂CH₃) 8.1 tert-Butyl8-(ethoxymethyl)-4-methyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate

A solution of 50 mg of(4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-8-yl)methanol(0.150 mmol, 1.00 eq) from step 6.2 in DMF (5 mL) was cooled to 0° C.Then 9.02 mg of sodium hydride (0.226 mmol, 1.50 eq) was added and themixture was stirred for 1 h at 0° C. 28.1 mg iodoethane (0.180 mmol,1.20 eq) was added and the mixture was stirred for 72 h at roomtemperature. Then the solvent was evaporated and the crude product waspurified via preparative HPLC to yield the title compound.

ESI-MS: m/z (%): 361.50 (100, [M+H]⁺).

8.28-(Ethoxymethyl)-4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

To a solution of 23.2 mg of tert-butyl8-(ethoxymethyl)-4-methyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate(0.064 mmol, 1.00 eq) from step 8.1 in DCM (5 mL) was added 99.0 μL ofTFA (1.29 mmol, 20 eq) and the mixture was stirred for 24 h at roomtemperature. Then the solvent was evaporated and the crude product waspurified via prep-HPLC to yield the title compound (10%, 0.006 mmol).

ESI-MS: m/z (%): 261.20 (100, [M+H]⁺).

¹H NMR (500 MHz, Methanol-d₄): δ 7.36-7.20 (m, 1H), 7.16 (dd, J=7.4, 1.6Hz, 1H), 6.91 (t, J=7.6 Hz, 1H), 4.28 (d, J=13.1 Hz, 1H), 4.11-3.99 (m,1H), 3.72-3.60 (m, 1H), 3.63-3.44 (m, 4H), 3.33-3.16 (m, 4H), 3.08-2.99(m, 1H), 2.05-1.92 (m, 1H), 1.92-1.80 (m, 1H), 1.27-1.13 (m, 6H).

Example 98-(Methoxymethyl)-4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline(Compound of Formula Ia.10 Wherein R^(4a), R^(4b), R^(5a), R^(5b) andR^(7a) are hydrogen and R⁶ is methoxymethyl (CH₂OCH₃) 9.1 tert-Butyl8-(methoxymethyl)-4-methyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate

A solution of 50 mg of(4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-8-yl)methanol(0.150 mmol, 1.00 eq) from step 6.2 in DMF (5 mL) was cooled to 0° C.Then 9.02 mg of sodium hydride (0.226 mmol, 1.50 eq) was added and themixture was stirred for 1 h at 0° C. 32.3 mg of iodomethane (0.226 mmol,1.50 eq) was added and the mixture was stirred for 72 h at roomtemperature. Then the solvent was evaporated and the crude product waspurified via column chromatography on silica (eluent: 0-40% methanol inDCM) which yielded the title compound (80%, 0.120 mmol).

ESI-MS: m/z (%): 347.30 (100, [M+H]⁺).

9.28-(Methoxymethyl)-4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

To a solution of 41.6 mg of tert-butyl8-(methoxymethyl)-4-methyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate(0.120 mmol, 1.00 eq) from step 9.1 in DCM (5 mL) was added 185 μL ofTFA (2.40 mmol, 20.0 eq) and the mixture was stirred for 24 h at roomtemperature. Then the solvent was evaporated and the crude product waspurified via preparative HPLC to yield the title compound (19%, 0.023mmol).

ESI-MS: m/z (%): 247.30 (100, [M+H]⁺).

¹H NMR (500 MHz, Methanol-d₄): δ ¹H NMR (500 MHz, Methanol-d₄) δ7.31-7.25 (m, 1H), 7.16 (dd, J=7.6, 1.6 Hz, 1H), 6.91 (t, J=7.6 Hz, 1H),4.28 (d, J=13.2 Hz, 1H), 4.04 (d, J=13.2 Hz, 1H), 3.61-3.54 (m, 1H),3.57-3.49 (m, 2H), 3.37 (s, 3H), 3.28-3.18 (m, 3H), 3.25-3.22 (m, 2H),3.08-3.01 (m, 1H), 2.03-1.94 (m, 1H), 1.91-1.80 (m, 1H), 1.24 (d, J=7.0Hz, 3H).

II. Biological Tests

Functional Activity

1. Human 5-HT_(2C) Functional Assay

The functional activity of compounds of formula I was assayed byincubation with U2OS_HTR_(2C) _(_)β-Arrestin cells (DiscoverX,93-0289C3) to induce beta-arrestin2 recruitment to the 5-HT_(2C)receptor. The agonist-induced recruitment and proximity of the receptorand beta-arrestin2 leads to complementation and formation of activeβ-galactosidase. The enzyme complementation results in enzyme activity,which is measured following the termination of the agonist incubationusing DiscoveRx's detection reagent, which contains a chemiluminescentsubstrate which produces a high intensity signal. Cells were plated anda medium-change to a 1% serum containing medium was performed 24 hlater. The next day, test compounds were added and incubated for 1.5 hbefore addition of detection reagent.

The response produced was measured and compared with the responseproduced by 10 [mu]M 5-HT or the maximal effect induced by 5-HT (definedas 100%) to which it was expressed as a percentage response (relativeefficacy). Dose response curves were constructed using Graphpad Prism(Graph Software Inc.) or using in house adapted software using a 4parameter dose response model with variable slope(fit=(Bottom+(Top-Bottom)/(1+10̂((LogEC50-x)*HillSlope))res=(y-fit)).Results are compiled in the table below.

2. Human 5-HT_(2A) Functional Assay

Functional activity on the 5-HT_(2A) receptor was determined by testingthe effect of the compounds I on calcium mobilization in CHO-K1 cells,stably transfected with human 5-HT_(2A) receptor. Cells were seeded intosterile black 384-well plates with clear bottom at 25,000 cells/well ina volume of 25 μl and grown for 5-6 hours at 37° C., in 5% CO₂ in tissueculture medium (“Ultra CHO” by LONZA), containing 1% dialysed FCS and 50μg/ml gentamicin (Invitrogen). After this incubation, medium wasreplaced by a serum free version of the same tissue culture mediumfollowed by incubation overnight at 37° C. and in 5% CO₂. Cells werethen loaded with a fluorescent calcium-sensitive dye in the presence of0.07% probenecid for an hour at 37° C., according to the manufacturer'sprotocol (Ca5-Assay Kit, Molecular Devices), followed by an additional60 min incubation at room temperature. Serial compound dilutions (finalconcentrations of 10⁻¹⁰ to 10⁻⁵ M, prepared in HBSS+50 HEPES) were firstadded to the cells alone (“first addition” to assess agonism on the5-HT_(2A) receptor), then after 8 min, serotonin was added to the samewells at a final concentration of 3×10⁻⁸M (“second addition” to seepotential antagonistic effect) and the maximal calcium response wasdetermined using a FLIPR® Tetra instrument (Molecular Devices) in eachof the two steps. The relative efficacy of the compounds was calculatedas a percentage of the maximal effect induced by serotonin alone(defined as 100%). To determine EC₅₀/IC₅₀ values, concentration-responsecurves were fitted using a four-parameter logistic equation (IDBSBiobook™). K_(b) values were calculated from IC₅₀ values, according toCheng & Prusoff.

3. Human 5-HT_(2B) Functional Assay

Functional activity on the 5-HT_(2B) receptor was determined by testingthe effect of the compounds I on calcium mobilization in CHO-FlpIncells, stably transfected with human 5-HT_(2B) receptor. Cells wereseeded into sterile black 384-well plates with clear bottom at 30,000cells/well in a volume of 25 μl and grown overnight at 37° C., in 5% CO₂in tissue culture medium (“CHO-S-SFM II” by Invitrogen), containing 1%dialysed FCS and 50 μg/ml gentamicin (Invitrogen). On the next morning,medium was replaced by a serum free version of the same tissue culturemedium for a further incubation for 4 hours at 37° C. and in 5% CO₂.Cells were then loaded with a fluorescent calcium-sensitive dye in thepresence of 0.07% probenecid for an hour at 37° C., according to themanufacturer's protocol (Ca5-Assay Kit, Molecular Devices), followed byan additional 60 min incubation at room temperature. Serial compounddilutions (final concentrations of 10⁻¹⁰ to 10⁻⁵M, prepared in HBSS+50mM HEPES) were first added to the cells alone (“first addition” toassess agonism on the 5-HT_(2B) receptor), then after 8 min, serotoninwas added to the same wells at a final concentration of 10⁻⁸ M (“secondaddition” to see potential antagonistic effect) and the maximal calciumresponse was determined using a FLIPR® Tetra instrument (MolecularDevices) in each of the two steps. The relative efficacy of thecompounds was calculated as a percentage of the maximal effect inducedby serotonin alone (defined as 100%). To determine EC₅₀/IC₅₀ values,concentration-response curves were fitted using a four-parameterlogistic equation (IDBS Biobook™). K_(b) values were calculated fromIC₅₀ values, according to Cheng & Prusoff.

TABLE Selec- EC50 % EC50 % Selectivity⁴ EC50 % tivity⁵ 5- effi- 5- effi-(based on 5- effi- (based on # HT_(2C) ¹ cacy HT_(2A) ² cacy agonism)HT_(2B) ³ cacy agonism) 1 ++ 85 *  antagonist⁶ * antagonist 1.A ++ 57 *antagonist * antagonist 1.B ++ 88 * antagonist + 34 3 2 + 72 * full⁷ *antagonist 3 ++ 93 * antagonist * full 4 ++ 104 * antagonist *antagonist 4.A +++ 101 * antagonist * antagonist 4.B ++ 87 *antagonist * antagonist 4.C +++ 101 ++ 24 2 ++ 44 12 4.D + 86 *antagonist + 30 2 5 ++ 95 * antagonist * antagonist 5.A +++ 109 +++ 210.5 + 36 20 5.B ++ 110 * antagonist * antagonist 5.C + 89 * full *antagonist 5.D + 84 * full * antagonist 7 ++ 107 * antagonist *antagonist 8 + 93 * full * full 9 + 82 * full * full ¹Potency (EC505-HT_(2C)) in functional assay ²Potency (EC50 5-HT_(2A)) in functionalassay ³Potency (EC50 5-HT_(2B)) in functional assay ⁴EC50 5-HT_(2A)/EC505-HT_(2C) ⁵EC50 5-HT_(2B)/EC50 5-HT_(2C) ⁶“antagonist” indicatesfunctional antagonism with no measurable agonistic effect ⁷“full”indicates no measurable agonistic effect at 10 μM (highest concentrationin assay) Potency (EC50): * >10 μM + from 200 nM to <1 μM ++ from 20 nMto <200 nM +++ <20 nM

1.-39. (canceled)
 40. A method for treating disorders which respond tothe modulation of the 5-HT_(2c) receptor comprising administering to asubject in need thereof at least one compound of formula (I)

wherein R¹ is selected from the group consisting of hydrogen, cyano,C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl, fluorinatedC₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,fluorinated C₁-C₆-alkoxy, —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl and a 3-,4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated ormaximally unsaturated heterocyclic ring containing 1, 2, 3 or 4heteroatoms or heteroatom groups independently selected from N, O, S,NO, SO and SO₂ and optionally also 1 or 2 C═O and/or C═S groups as ringmembers, where the cyclic moieties in the three last-mentioned radicalsmay be substituted with one or more substituents R¹⁰; each R² isindependently selected from the group consisting of cyano, nitro,C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl,fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl,—CH₂NR^(11a)R^(11b), —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl, and a 3-, 4-,5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximallyunsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatomgroups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S asring members, where the cyclic moieties in the six last-mentionedradicals may be substituted with one or more substituents R¹⁰; or tworadicals R² bound to the same carbon atom, together with the carbon atomthey are bound to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated,partially unsaturated or maximally unsaturated ring, where the ring maycontain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groupsselected from O, S, N, SO, SO₂, C═O and C═S as ring members, and wherethe ring may be substituted with one or more substituents R¹⁰; R^(3a)and R^(3b), independently of each other, are selected from the groupconsisting of hydrogen, cyano, nitro, C₁-C₆-alkyl, fluorinatedC₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinatedC₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl,—CH₂NR^(11a)R^(11b), —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl, and a 3-, 4-,5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximallyunsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatomgroups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S asring members, where the cyclic moieties in the six last-mentionedradicals may be substituted with one or more substituents R¹⁰; R^(4a)and R^(4b), independently of each other, are selected from the groupconsisting of hydrogen, cyano, nitro, C₁-C6-alkyl, fluorinatedC₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinatedC₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl,—CH₂NR^(11a)R^(11b), —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl, and a 3-, 4-,5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximallyunsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatomgroups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S asring members, where the cyclic moieties in the six last-mentionedradicals may be substituted with one or more substituents R¹⁰; or R^(4a)and R^(4b) form together a group ═O or ═S; or R^(4a) and R^(4b),together with the carbon atom they are bound to, form a 3-, 4-, 5-, 6-,7- or 8-membered saturated, partially unsaturated or maximallyunsaturated ring, where the ring may contain 1, 2, 3 or 4 heteroatoms orheteroatom-containing groups selected from O, S, N, SO, SO₂, C═O and C═Sas ring members, and where the ring may be substituted with one or moresubstituents R¹⁰; R^(5a) and R^(5b), independently of each other, areselected from the group consisting of hydrogen, halogen, cyano, nitro,hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl,C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinatedC₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl,fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-hydroxyalkoxy,C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, fluorinated C₁-C₆-alkylsulfinyl,C₁-C₆-alkylsulfonyl, fluorinated C₁-C₆-alkylsulfonyl, —NR^(11a)R^(11b),—CH₂NR^(11a)R^(11b), —NR^(11a)C(O)R⁹, —C(═O)R⁹, SO₂NR^(11a)R^(11b),C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy, phenyl,phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-, 5-,6-, 7- or 8-membered saturated, partially unsaturated or maximallyunsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatomgroups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S asring members, where the cyclic moieties in the six last-mentionedradicals may be substituted with one or more substituents R¹⁰; whereR^(5a) and R^(5b) are not simultaneously hydroxyl; or R^(5a) and R^(5b),together with the carbon atom they are bound to, form a 3-, 4-, 5-, 6-,7- or 8-membered saturated, partially unsaturated or maximallyunsaturated ring, where the ring may contain 1, 2, 3 or 4 heteroatoms orheteroatom-containing groups selected from O, S, N, SO, SO₂, C═O and C═Sas ring members, and where the ring may be substituted with one or moresubstituents R¹⁰; R⁶ is C₁-C₆-alkyl which carries one or moresubstituents R⁸; each R⁷ is independently selected from the groupconsisting of halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl, fluorinatedC₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinatedC₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl,fluorinated C₃-C₈-cycloalkenyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl,C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio,fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinatedC₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinatedC₁-C₆-alkylsulfonyl, —NR^(11a)R^(11b), —CH₂NR^(11a)R^(11b),—NR^(11a)C(O)R⁹, —C(═O)R⁹, SO₂NR^(11a)R^(11b), C₁-C₆-alkylcarbonyloxy,fluorinated C₁-C₆-alkylcarbonyloxy, phenyl, phenyl-C₁-C₂-alkyl, phenoxy,phenylsulfonyl, benzyloxy and a 3-, 4-, 5-, 6-, 7- or 8-memberedsaturated, partially unsaturated or maximally unsaturated ringcontaining 1, 2, 3 or 4 heteroatoms or heteroatom groups independentlyselected from N, O, S, NO, SO, SO₂, C═O and C═S as ring members, wherethe cyclic moieties in the six last-mentioned radicals may besubstituted with one or more substituents R¹⁰; or two radicals R⁷ boundon neighboring carbon atoms, together with the carbon atoms they arebound to, form a 3-, 4-, 5-, 6-, 7- or 8-membered partially unsaturatedor maximally unsaturated ring, where the ring may contain 1, 2, 3 or 4heteroatoms or heteroatom-containing groups selected from O, S, N, SO,SO₂, C═O and C═S as ring members, and where the ring may be substitutedwith one or more substituents R¹⁰; each R⁸ is independently selectedfrom the group consisting of hydroxyl, halogen, C₁-C₆-alkoxy,fluorinated C₁-C₆-alkoxy, C₁-C₆-hydroxyalkoxy,C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, fluorinated C₁-C₆-alkylsulfinyl,C₁-C₆-alkylsulfonyl, fluorinated C₁-C₆-alkylsulfonyl and—NR^(11a)R^(11b); each R⁹ is independently selected from the groupconsisting of hydrogen, cyano, hydroxyl, C₁-C₆-alkyl, fluorinatedC₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinatedC₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl,C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy,fluorinated C₁-C₆-alkoxy, —NR^(11a)R^(11b), —CH₂NR^(11a)R^(11b), phenyl,phenyl-C₁-C₂-alkyl, phenoxy, benzyloxy and a 3-, 4-, 5-, 6-, 7- or8-membered saturated, partially unsaturated or maximally unsaturatedring containing 1, 2, 3 or 4 heteroatoms or heteroatom groupsindependently selected from N, O, S, NO, SO, SO₂, C═O and C═S as ringmembers, where the cyclic moieties in the five last-mentioned radicalsmay be substituted with one or more substituents R¹⁰; each R¹⁰ isindependently selected from the group consisting of halogen, cyano,nitro, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl,C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinatedC₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl,C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio,fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinatedC₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinatedC₁-C₆-alkylsulfonyl, —COOH, —NR^(11a)R^(11b), —CH₂NR^(11a)R^(11b),C₁-C₆-alkylcarbonyl, fluorinated C₁-C₆-alkylcarbonyl,C₁-C₆-alkoxycarbonyl, fluorinated C₁-C₆-alkoxycarbonyl,SO₂NR^(11a)R^(11b), C₁-C₆-alkylcarbonyloxy and fluorinatedC₁-C₆-alkylcarbonyloxy; or two radicals R¹⁰, together with the atom(s)they are bound to, form a saturated, partially unsaturated or maximallyunsaturated 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclicring, where the heterocyclic ring contains 1, 2 or 3 heteroatoms orheteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═Oand C═S as ring members; R^(11a) and R^(11b), independently of eachother and independently of each occurrence, are selected from the groupconsisting of hydrogen, cyano, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl,C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinatedC₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl,C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl, fluorinatedC₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, fluorinatedC₁-C₆-alkoxycarbonyl, phenyl and benzyl, where the phenyl moieties inthe two last-mentioned radicals may carry 1, 2 or 3 substituentsselected from halogen, cyano nitro, C₁-C₆-alkyl, fluorinatedC₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy; or, if R^(11a)and R^(11b) are bound to the same nitrogen atom, together with thisnitrogen atom may form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated,partially unsaturated or maximally unsaturated heterocyclic ring, wherethe ring may further contain 1, 2, 3 or 4 heteroatoms orheteroatom-containing groups selected from O, S, N, SO, SO₂, C═O and C═Sas ring members, and where the ring may be substituted with one or moresubstituents selected from halogen, cyano nitro, C₁-C₆-alkyl,fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy; a is0, 1 or 2; and b is 0, 1, 2 or 3; or an N-oxide, a tautomeric form, astereoisomer or a pharmaceutically acceptable salt thereof.
 41. Themethod as claimed in claim 40, where the disorders are selected from thegroup consisting of damage of the central nervous system, disorders ofthe central nervous system, eating disorders, ocular hypertension,cardiovascular disorders, gastrointestinal disorders and diabetes. 42.The method as claimed in claim 41, where the disorders are selected fromthe group consisting of bipolar disorder, depression, atypicaldepression, mood episodes, adjustment disorders, anxiety, panicdisorders, post-traumatic syndrome, psychoses, schizophrenia, cognitivedeficits of schizophrenia, memory loss, dementia of aging, Alzheimer'sdisease, neuropsychiatric symptoms in Alzheimer's disease, behavioraldisorders associated with dementia, social phobia, mental disorders inchildhood, attention deficit hyperactivity disorder, organic mentaldisorders, autism, mutism, disruptive behavior disorder, impulse controldisorder, borderline personality disorder, obsessive compulsivedisorder, migraine and other conditions associated with cephalic pain orother pain, raised intracranial pressure, seizure disorders, epilepsy,substance use disorders, alcohol abuse, cocaine abuse, tobacco abuse,smoking cessation, sexual dysfunction/erectile dysfunction in males,sexual dysfunction in females, premenstrual syndrome, late luteal phasesyndrome, chronic fatigue syndrome, sleep disorders, sleep apnoea,chronic fatigue syndrome, psoriasis, Parkinson's disease, psychosis inParkinson's disease, neuropsychiatric symptoms in Parkinson's disease,Lewy Body dementia, neuropsychiatric symptoms in Lewy Body dementia,spinal cord injury, trauma, stroke, pain, bladder dysfunction/urinaryincontinence, encephalitis, meningitis, eating disorders, obesity,bulimia, weight loss, anorexia nervosa, ocular hypertension,cardiovascular disorders, gastrointestinal disorders, diabetesinsipidus, diabetes mellitus, type I diabetes, type II diabetes, typeIII diabetes, diabetes secondary to pancreatic diseases, diabetesrelated to steroid use, diabetes complications, hyperglycemia andinsulin resistance.
 43. The method as claimed in claim 42, where thedisorders are selected from the group consisting of schizophrenia,depression, bipolar disorders, obesity, substance use disorders,neuropsychiatric symptoms in Alzheimer's disease and neuropsychiatricsymptoms in Parkinson's disease.
 44. The method as claimed in claim 40,where R¹ is hydrogen.
 45. The method as claimed in claim 40, where R² isselected from methyl and CF₃.
 46. The method as claimed in claim 40,where R^(3a) and R^(3b) are hydrogen.
 47. The method as claimed in claim40, where R^(4a) and R^(4b) are hydrogen.
 48. The method as claimed inclaim 40, where R^(5a) is hydrogen or methyl and R^(5b) is hydrogen 49.The method as claimed in claim 40, where each R⁸ is independentlyselected from the group consisting of halogen, C₁-C₆-alkoxy andfluorinated C₁-C₆-alkoxy.
 50. The method as claimed in claim 40, whereR⁶ is fluorinated C₁-C₂-alkyl.
 51. The method as claimed in claim 40,where R⁶ is fluorinated methyl.
 52. The method as claimed in claim 40,where R⁶ is CHF₂ or CF₃.
 53. The method as claimed in claim 40, where R⁶is C₁-C₄-alkoxy-methyl.
 54. The method as claimed in claim 40, where R⁶is C₁-C₄-alkyl which carries a hydroxyl substituent.
 55. The method asclaimed in claim 40, where a is 0 or
 1. 56. The method as claimed inclaim 40, where in case that a is 1, R² is bound in β-position to thenitrogen ring atom carrying R¹.
 57. The method as claimed in claim 40,where b is 0 or
 1. 58. The method as claimed in claim 40, wherein the atleast one compound of formula (I) is at least one compound of formula(I1.1)

where R^(7a) is H, Cl, F or methyl; a is 0 or 1; and R², R⁶, R⁷ and bare as defined as in claim
 40. 59. A method for treating disorders whichrespond to the modulation of the 5-HT_(2c) receptor comprisingadministering to a subject in need thereof at least one compoundselected from the group consisting of8-(Trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;(S)-8-(Trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;(R)-8-(Trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;8-(2,2,2-Trifluoroethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;(S)-8-(2,2,2-Trifluoroethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;(R)-8-(2,2,2-Trifluoroethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;8-(Difluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;(S)-8-(Difluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;(R)-8-(Difluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;4-Methyl-8-(trifluoromethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;8-(Difluoromethyl)-4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;(4-Methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolin-8-yl)methanol;8-(Fluoromethyl)-4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;8-(Ethoxymethyl)-4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;and8-(Methoxymethyl)-4-methyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;and stereoisomers and pharmaceutically acceptable salts thereof.
 60. Themethod as claims in claim 59, where the disorders are selected from thegroup consisting of damage of the central nervous system, disorders ofthe central nervous system, eating disorders, ocular hypertension,cardiovascular disorders, gastrointestinal disorders and diabetes. 61.The method as claims in claim 60, where the disorders are selected fromthe group consisting of bipolar disorder, depression, atypicaldepression, mood episodes, adjustment disorders, anxiety, panicdisorders, post-traumatic syndrome, psychoses, schizophrenia, cognitivedeficits of schizophrenia, memory loss, dementia of aging, Alzheimer'sdisease, neuropsychiatric symptoms in Alzheimer's disease, behavioraldisorders associated with dementia, social phobia, mental disorders inchildhood, attention deficit hyperactivity disorder, organic mentaldisorders, autism, mutism, disruptive behavior disorder, impulse controldisorder, borderline personality disorder, obsessive compulsivedisorder, migraine and other conditions associated with cephalic pain orother pain, raised intracranial pressure, seizure disorders, epilepsy,substance use disorders, alcohol abuse, cocaine abuse, tobacco abuse,smoking cessation, sexual dysfunction/erectile dysfunction in males,sexual dysfunction in females, premenstrual syndrome, late luteal phasesyndrome, chronic fatigue syndrome, sleep disorders, sleep apnoea,chronic fatigue syndrome, psoriasis, Parkinson's disease, psychosis inParkinson's disease, neuropsychiatric symptoms in Parkinson's disease,Lewy Body dementia, neuropsychiatric symptoms in Lewy Body dementia,spinal cord injury, trauma, stroke, pain, bladder dysfunction/urinaryincontinence, encephalitis, meningitis, eating disorders, obesity,bulimia, weight loss, anorexia nervosa, ocular hypertension,cardiovascular disorders, gastrointestinal disorders, diabetesinsipidus, diabetes mellitus, type I diabetes, type II diabetes, typeIII diabetes, diabetes secondary to pancreatic diseases, diabetesrelated to steroid use, diabetes complications, hyperglycemia andinsulin resistance.
 62. The method as claimed in claim 61, where thedisorders are selected from the group consisting of schizophrenia,depression, bipolar disorders, obesity, substance use disorders,neuropsychiatric symptoms in Alzheimer's disease and neuropsychiatricsymptoms in Parkinson's disease.